Neuropeptide Y Y5 receptor antagonists

ABSTRACT

The present invention discloses compounds which, are novel receptor antagonists for NPY Y5 as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such NPY Y5 receptor antagonists as well as methods of using them to treat obesity, metabolic disorders, eating disorders such as hyperphagia, and diabetes.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/308,433 filed on Jul. 26, 2001.

FIELD OF THE INVENTION

[0002] The present invention relates to neuropeptide Y Y5 receptorantagonists useful in the treatment of obesity and eating disorders,pharmaceutical compositions containing the compounds, and methods oftreatment using the compounds.

BACKGROUND OF THE INVENTION

[0003] Neuropeptide Y (NPY) is a 36 amino acid neuropeptide that iswidely distributed in the central and peripheral nervous systems. NPY isa member of the pancreatic polypeptide family that also includes peptideYY and pancreatic polypeptide (Wahlestedt, C., and Reis, D., Ann. Rev.Toxicol., 32, 309,1993). NPY elicits its physiological effects byactivation of at least six receptor subtypes designated Y1, Y2, Y3, Y4,Y5 and Y6 (Gehlert, D., Proc. Soc. Exp. Biol. Med., 218, 7, 1998;Michel, M. et al., Pharmacol. Rev., 50, 143, 1998). Centraladministration of NPY to animals causes dramatically increased foodintake and decreased energy expenditure (Stanley, B. and Leibowitz, S.,Proc. Natl. Acad. Sci. USA 82: 3940, 1985; Billington et al., Am J.Physiol., 260, R321, 1991). These effects are believed to be mediated atleast in part by activation of the NPY Y5 receptor subtype. Theisolation and characterization of the NPY Y5 receptor subtype has beenreported (Gerald, C. et al., Nature, 1996, 382,168; Gerald, C. et al. WO96/16542). Additionally, it has been reported that activation of the NPYY5 receptor by administration of the Y5-selective agonist [D-Trp³²]NPYto rats stimulates feeding and decreases energy expenditure (Gerald, C.et al., Nature, 1996, 382,168; Hwa, J. et al., Am. J. Physiol., 277(46), R1428, 1999). Hence, compounds that block binding of NPY to theNPY Y5 receptor subtype should have utility in the treatment of obesity,disorders such as, bulimia nervosa, anorexia nervosa, and in thetreatment of disorders associated with obesity such as type II diabetes,insulin resistance, hyperlipidemia, and hypertension.

[0004] PCT patent application WO 00/27845 describes a class ofcompounds, characterized therein as spiro-indolines, said to beselective neuropeptide Y Y5 receptor antagonists and useful for thetreatment of obesity and the complications associated therewith. Ureaderivatives indicated as possessing therapeutic activity are describedin U.S. Pat. Nos. 4,623,662 (antiatherosclerotic agents) and 4,405,644(treatment of lipometabolism).

[0005] Provisional application, U.S. Ser. No. 60/232,255 describes aclass of substituted urea neuropeptide Y Y5 receptor antagonists.

SUMMARY OF THE INVENTION

[0006] In one embodiment, this invention provides novel urea compoundshaving NPY Y5 receptor antagonist activity. In an embodiment of theinvention is a compound represented by the structural formula

[0007] or a pharmaceutically acceptable salt or solvate thereof,wherein:

[0008] X is independently N or C;

[0009] Z is independently NR⁸ or CR³R⁹;

[0010] D is independently H, —OH, -alkyl or substituted -alkyl with theproviso that when X is N, D and the X-D bond are absent;

[0011] E is independently H, -alkyl or substituted -alkyl, or D and Ecan independently be joined together via a —(CH₂)_(p)— bridge;

[0012] Q is independently H, -alkyl or substituted -alkyl, or D, X, Qand the carbon to which Q is shown attached can jointly form a 3 to7-membered ring;

[0013] g, j, k, m and n can be the same or different and areindependently selected;

[0014] g is 0 to 3 and when g is 0, the carbons to which (CH₂)_(g) isshown connected are no more linked;

[0015] j and k are independently 0 to 3 such that the sum of j and k is0, 1, 2 or 3;

[0016] m and n are independently 0 to 3 such that the sum of m and n is1, 2,3, 4 or 5;

[0017] p is 1 to 3;

[0018] R¹ is 1 to 5 substituents which can be the same or different,each R¹ being independently selected from the group consisting ofhydrogen, hydroxy, halogen, haloalkyl, -alkyl, substituted -alkyl,-cycloalkyl, CN, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, —NR⁵R⁶,—NO₂, —CONR⁵R⁶, —NR⁵COR⁶, —NR⁵CONR⁵R⁶ where the two R⁵ moieties can bethe same or different, —NR⁶C(O)OR⁷, —C(O)OR⁶, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶,aryl and heteroaryl;

[0019] R² is 1 to 6 substituents which can be the same or different,each R² being independently selected from the group consisting ofhydrogen, -alkyl, substituted -alkyl, alkoxy, and hydroxy, with theproviso that when X is N and R² is hydroxy or alkoxy, R² is not directlyattached to a carbon adjacent to X;

[0020] R³ is independently hydrogen, -alkyl or substituted -alkyl;

[0021] R⁴ is 1 to 6 substituents which can be the same or different,each R⁴ being independently selected from hydrogen, -alkyl, substituted-alkyl, alkoxy, and hydroxy, with the proviso that when Z is NR⁸ and R⁴is hydroxy or alkoxy, R⁴ is not directly attached to a carbon adjacentto the NR⁸;

[0022] R⁵ and R⁶ are independently hydrogen, -alkyl, substituted -alkylor -cycloalkyl;

[0023] R⁷ is independently -alkyl, substituted -alkyl or -cycloalkyl;

[0024] R⁸ is independently selected from the group consisting ofhydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl,aryl, heteroaryl, aralkyl, heteroaralkyl, —SO₂R¹⁰, —SO₂NR⁵R¹¹, —C(O)R¹¹,—C(O)NR⁵R¹¹ and —C(O)OR¹⁰;

[0025] R⁹ is independently hydrogen, -alkyl, substituted -alkyl,hydroxy, alkoxy, —NR⁵R¹¹, aryl, or heteroaryl; or R³ and R⁹ can bejoined together and with the carbon to which they are attached form acarbocyclic or heterocyclic ring having 3 to 7 ring atoms;

[0026] R¹⁰ is -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl,aryl or heteroaryl; and

[0027] R¹¹ is independently hydrogen, -alkyl, substituted -alkyl,-cycloalkyl, aryl or heteroaryl.

[0028] The above statement “when g is 0, the carbons to which (CH₂)_(g)is shown connected are no more linked” means that when g is 0, then thestructural component:

[0029] shown in formula I above becomes:

[0030] Ureas of formula I or formula III are highly selective, highaffinity NPY Y5 receptor antagonists useful for the treatment ofobesity.

[0031] This invention is also directed to pharmaceutical compositionsfor the treatment of metabolic disorders such as obesity, and eatingdisorders such as hyperphagia. In one aspect, this invention is alsodirected to pharmaceutical compositions for the treatment of obesitywhich comprise an obesity treating amount of a compound of formula I orformula III thereof, or a pharmaceutically acceptable salt or solvate ofsaid compound, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

[0032] The present invention relates to compounds that are representedby structural formula I or formula III or a pharmaceutically acceptablesalt or solvate thereof, wherein the various moieties are as describedabove. The compounds of formula I or formula III can be administered asracemic mixtures or enantiomerically pure compounds.

[0033] In a preferred embodiment of the invention is a compound offormula I or a pharmaceutically acceptable salt or solvate thereof,wherein:

[0034] R¹ is 1 to 5 substituents which can be the same or different,each R¹ being independently selected from the group consisting of Cl,Br, I or F;

[0035] X is N;

[0036] D is absent and the X-D bond is absent;

[0037] E is H;

[0038] g is 0;

[0039] j is 1;

[0040] k is 1;

[0041] m is 2;

[0042] n is 2;

[0043] R² is H;

[0044] R³ is methyl;

[0045] R⁴ is H;

[0046] and

[0047] Z is NR⁸, where R⁸ is independently selected from the groupconsisting of hydrogen, -alkyl, substituted -alkyl, -cycloalkyl,-alkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —SO₂R¹⁰,—SO₂NR⁵R¹¹, —C(O)R¹¹, —C(O)NR⁵R¹¹ and —C(O)OR¹⁰.

[0048] A preferred embodiment of the present invention is a compound offormula II or a pharmaceutically acceptable salt or solvate thereof,wherein:

[0049] wherein R⁸ is defined as herein in the Detailed Description inTable 1.

[0050] An additional preferred embodiment of the present invention is acompound of formula III or a pharmaceutically acceptable salt or solvatethereof, wherein:

[0051] wherein

[0052] R¹ is 1 to 5 substituents which can be the same or different,each R¹ being independently selected from the group consisting ofhydrogen, hydroxy, halogen, haloalkyl, -alkyl, substituted -alkyl,-cycloalkyl, CN, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, —NR⁵R⁶,—NO₂, —CONR⁵R⁶, —NR⁵COR⁶, —NR⁵CONR⁵R⁶ where the two R⁵ moieties can bethe same or different, —NR⁶C(O)OR⁷, —C(O)OR⁶, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶,aryl and heteroaryl;

[0053] R³ is independently hydrogen or -alkyl; and

[0054] R⁸ is independently selected from the group consisting ofhydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl,aryl, heteroaryl, aralkyl, heteroaralkyl, —SO₂R¹⁰, —SO₂NR⁵R¹¹, —C(O)R¹¹,—C(O)NR⁵R¹¹ and —C(O)OR¹⁰.

[0055] A further preferred group of compounds are compounds of formulaIII selected from the group consisting of

[0056] or a pharmaceutically acceptable salt or solvate of saidcompound.

[0057] An additional preferred embodiment of the present invention is acompound of formula IV, wherein

[0058] or a pharmaceutically acceptable salt or solvate there of,wherein

[0059] R¹ is 1 to 5 substituents which can be the same or different,each R¹ being independently selected from the group consisting ofhydrogen, hydroxy, halogen, haloalkyl, -alkyl, substituted -alkyl,-cycloalkyl, CN, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, —NR⁵R⁶,—NO₂, —CONR⁵R⁶, —NR⁵COR⁶, —NR⁵CONR⁵R⁶ where the two R⁵ moieties can bethe same or different, —NR⁶C(O)OR⁷, —C(O)OR⁶, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶,aryl and heteroaryl;

[0060] R³ is independently hydrogen or -alkyl; and

[0061] R⁸ is independently selected from the group consisting ofhydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl,aryl, heteroaryl, aralkyl, heteroaralkyl, —SO₂R¹⁰, —SO₂NR⁵R¹¹, —C(O)R¹¹,—C(O)NR⁵R¹¹ and —C(O)OR¹⁰.

[0062] A set of preferred compounds are listed below in the DetailedDescription in Tables 2 and 3, among other preferred compounds.

[0063] Except where stated otherwise, the following definitions applythroughout the present specification and claims. These definitions applyregardless of whether a term is used by itself or in combination withother terms. Hence the definition of “alkyl” applies to “alkyl” as wellas to the “alkyl” portions of “alkoxy”, “alkylamino” etc.

[0064] As used above, and throughout the specification, the followingterms, unless otherwise indicated, shall be understood to have thefollowing meanings:

[0065] “Patient” includes both human and other mammals.

[0066] “Mammal” means humans and other animals.

[0067] “Alkyl” means an aliphatic hydrocarbon group, which may bestraight or branched and comprising about 1 to about 20 carbon atoms inthe chain. Preferred alkyl groups contain about 1 to about 12 carbonatoms in the chain. More preferred alkyl groups contain about 1 to about6 carbon atoms in the chain. Branched means that one or more lower alkylgroups such as methyl, ethyl or propyl, are attached to a linear alkylchain. “Lower alkyl” means an alkyl group having about 1 to about 6carbon atoms in the chain, which may be straight or branched. The term“substituted alkyl” means that the alkyl group may be substituted by oneor more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, -alkyl, aryl, -cycloalkyl, cyano, hydroxy, alkoxy, alkylthio,amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, carboxy and—C(O)O-alkyl. Non-limiting examples of suitable alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl.

[0068] “Alkenyl” means an aliphatic hydrocarbon group comprising atleast one carbon-carbon double bond and which may be straight orbranched and comprising about 2 to about 15 carbon atoms in the chain.Preferred alkenyl groups have about 2 to about 12 carbon atoms in thechain; and more preferably about 2 to about 6 carbon atoms in the chain.Branched means that one or more lower alkyl groups such as methyl, ethylor propyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansan alkenyl group having about 2 to about 6 carbon atoms in the chain,which may be straight or branched. The term “substituted alkenyl” meansthat the alkenyl group may be substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkyl, aryl, -cycloalkyl,cyano, and alkoxy. Non-limiting examples of suitable alkenyl groupsinclude ethenyl, propenyl, n-butenyl, and 3-methylbut-2-enyl.

[0069] “Alkynyl” means an aliphatic hydrocarbon group comprising atleast one carbon-carbon triple bond and which may be straight orbranched and comprising about 2 to about 15 carbon atoms in the chain.Preferred alkynyl groups have about 2 to about 12 carbon atoms in thechain; and more preferably about 2 to about 4 carbon atoms in the chain.Branched means that one or more lower alkyl groups such as methyl, ethylor propyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansan alkynyl group having about 2 to about 6 carbon atoms in the chain,which may be straight or branched. Non-limiting examples of suitablealkynyl groups include ethynyl, propynyl and 2-butynyl. The term“substituted alkynyl” means that the alkynyl group may be substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofalkyl, aryl and -cycloalkyl.

[0070] “Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be unsubstituted or substituted onthe ring with one or more substituents which may be the same ordifferent, each being independently selected from the group consistingof alkyl, aryl, —OCF₃, —OCOalkyl, —OCOaryl, —CF₃, heteroaryl, aralkyl,alkylaryl, heteroaralkyl, alkylheteroaryl, hydroxy, hydroxyalkyl,alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, haloalkyl, haloalkoxy,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio,heteroarylthio, aralkylthio, heteroaralkylthio, -cycloalkyl andheterocyclyl. Non-limiting examples of suitable aryl groups includephenyl and naphthyl. The “aryl” group can also be substituted by linkingtwo adjacent carbons on its aromatic ring via a combination of one ormore carbon atoms and one or more oxygen atoms such as, for example,methylenedioxy, ethylenedioxy, and the like.

[0071] “Heteroaryl” means an aromatic monocyclic or multicyclic ringsystem comprising about 5 to about 14 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the ring atoms is anelement other than carbon, for example nitrogen, oxygen or sulfur, aloneor in combination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted on the ring byreplacing an available hydrogen on the ring by one or more substituentswhich may be the same or different, each being independently selectedfrom the group consisting of alkyl, aryl, heteroaryl, aralkyl,alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio,heteroarylthio, aralkylthio, heteroaralkylthio, -cycloalkyl,cycloalkenyl and heterocyclyl. The prefix aza, oxa or thia before theheteroaryl root name means that at least a nitrogen, oxygen or sulfuratom respectively, is present as a ring atom. A nitrogen atom of aheteroaryl can be optionally oxidized to the corresponding N-oxide.Non-limiting examples of suitable heteroaryls include pyridyl,pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl,oxazolyl, thiazolyl, pyrrolyl, triazolyl, and the like.

[0072] “Aralkyl” means an aryl-alkyl- group in which the aryl and alkylare as previously described. Preferred aralkyls comprise a lower alkylgroup. Non-limiting examples of suitable aralkyl groups include benzyl,2-phenethyl and a naphthlenylmethyl. The bond to the parent moiety isthrough the alkyl.

[0073] “Alkylaryl” means an alkyl-aryl- group in which the alkyl andaryl are as previously described. Preferred alkylaryls comprise a loweralkyl group. A non-limiting example of a suitable alkylaryl groups istolyl. The bond to the parent moiety is through the aryl.

[0074] “Cycloalkyl” means a non-aromatic mono- or multicyclic ringsystem comprising about 3 to about 10 carbon atoms, preferably about 5to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 toabout 7 ring atoms. The cycloalkyl can be optionally substituted on thering by replacing an available hydrogen on the ring by one or moresubstituents which may be the same or different, each beingindependently selected from the group consisting of alkyl, aryl,heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl,alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy,aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkyl, cycloalkenyl and heterocyclyl.Non-limiting examples of suitable monocyclic cycloalkyls includecyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.Non-limiting examples of suitable multicyclic cycloalkyls include1-decalinyl, norbornyl, adamantyl and the like.

[0075] “Halo” means fluoro, chloro, bromo or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

[0076] “Halogen” means fluorine, chlorine, bromine or iodine. Preferredare fluorine, chlorine or bromine, and more preferred are fluorine andchlorine.

[0077] “Haloalkyl” means an alkyl as defined above wherein one or morehydrogen atoms on the alkyl is replaced by a halo group defined above.

[0078] “Cycloalkenyl” means a non-aromatic mono or multicyclic ringsystem comprising about 3 to about 10 carbon atoms, preferably about 5to about 10 carbon atoms which contains at least one carbon-carbondouble bond. Preferred cycloalkenyl rings contain about 5 to about 7ring atoms. The cycloalkenyl can be optionally substituted on the ringby replacing an available hydrogen on the ring by one or moresubstituents which may be the same or different, each beingindependently selected from the group consisting of alkyl, aryl,heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl,alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy,aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkyl, cycloalkenyl and heterocyclyl.Non-limiting examples of suitable monocyclic cycloalkenyls includecyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limitingexample of a suitable multicyclic cycloalkenyl is norbornylenyl.

[0079] “Heterocyclyl” means a non-aromatic saturated monocyclic ormulticyclic ring system comprising about 3 to about 10 ring atoms,preferably about 5 to about 10 ring atoms, in which one or more of theatoms in the ring system is an element other than carbon, for examplenitrogen, oxygen or sulfur, alone or in combination. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. The heterocyclyl can be optionally substituted on the ring byreplacing an available hydrogen on the ring by one or more substituentswhich may be the same or different, each being independently selectedfrom the group consisting of alkyl, aryl, heteroaryl, aralkyl,alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio,heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyland heterocyclyl. The nitrogen or sulfur atom of the heterocyclyl can beoptionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, pyranyl,tetrahydrothiophenyl, morpholinyl and the like.

[0080] “Aralkenyl” means an aryl-alkenyl- group in which the aryl andalkenyl are as previously described. Preferred aralkenyls contain alower alkenyl group. Non-limiting examples of suitable aralkenyl groupsinclude 2-phenethenyl and 2-naphthylethenyl. The bond to the parentmoiety is through the alkenyl.

[0081] “Heteroaralkyl” means a heteroaryl-alkyl- group in which theheteroaryl and alkyl are as previously described. Preferredheteroaralkyls contain a lower alkyl group. Non-limiting examples ofsuitable aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl andquinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

[0082] “Heteroaralkenyl” means an heteroaryl-alkenyl- group in which theheteroaryl and alkenyl are as previously described. Preferredheteroaralkenyls contain a lower alkenyl group. Non-limiting examples ofsuitable heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and2-(quinolin-3-yl)ethenyl. The bond to the parent moiety is through thealkenyl.

[0083] “Hydroxyalkyl” means a HO-alkyl- group in which alkyl is aspreviously defined. Preferred hydroxyalkyls contain lower alkyl.Non-limiting examples of suitable hydroxyalkyl groups includehydroxymethyl and 2-hydroxyethyl.

[0084] “Acyl” means an H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—,Alkynyl-C(O)—, cycloalkyl-C(O)—, cycloalkenyl-C(O)—, orcycloalkynyl-C(O)— group in which the various groups are as previouslydescribed. The bond to the parent moiety is through the carbonyl.Preferred acyls contain a lower alkyl. Non-limiting examples of suitableacyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, andcyclohexanoyl.

[0085] “Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1- and 2-naphthoyl.

[0086] “Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy and isopropoxy. The alkyl group islinked to an adjacent moiety through the ether oxygen.

[0087] “Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

[0088] “Alkylthio” means an alkyl-S— group in which the alkyl group isas previously described. Non-limiting examples of suitable alkylthiogroups include methylthio, ethylthio, i-propylthio and heptylthio. Thebond to the parent moiety is through the sulfur.

[0089] “Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

[0090] “Aralkylthio” means an aralkyl-S— group in which the aralkylgroup is as previously described. Non-limiting example of a suitablearalkylthio group is benzylthio. The bond to the parent moiety isthrough the sulfur.

[0091] “Alkoxycarbonyl” means an alkoxy group defined earlier linked toan adjacent moiety through a carbonyl. Non-limiting examples ofalkoxycarbonyl groups include —C(O)—CH₃, —C(O)—CH₂CH₃ and the like.

[0092] “Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limitingexamples of suitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

[0093] “Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limitingexample of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. Thebond to the parent moiety is through the carbonyl.

[0094] “Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups arethose in which the alkyl group is lower alkyl. The bond to the parentmoiety is through the sulfonyl.

[0095] “Alkylsulfinyl” means an alkyl-S(O)— group. Preferred groups arethose in which the alkyl group is lower alkyl. The bond to the parentmoiety is through the sulfinyl.

[0096] “Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parentmoiety is through the sulfonyl.

[0097] “Arylsulfinyl” means an aryl-S(O)— group. The bond to the parentmoiety is through the sulfinyl.

[0098] The term “optionally substituted” means optional substitutionwith the specified groups, radicals or moieties.

[0099] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

[0100] Solvates of the compounds of the invention are also contemplatedherein.

[0101] “Solvate” means a physical association of a compound of thisinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. “Solvate”encompasses both solution-phase and isolatable solvates. Non-limitingexamples of suitable solvates include ethanolates, methanolates, and thelike. “Hydrate” is a solvate wherein the solvent molecule is H₂O.

[0102] “Effective amount” or “therapeutically effective amount” is meantto describe an amount of compound of the present invention effective totreat a mammal (e.g., human) having a disease or condition mediated by YY5, and thus producing the desired therapeutic effect.

[0103] The compounds of formula I or formula III form salts which arealso within the scope of this invention. Reference to a compound offormula I or formula III, herein is understood to include reference tosalts thereof, unless otherwise indicated. The term “salt(s)”, asemployed herein, denotes acidic salts formed with inorganic and/ororganic acids, as well as basic salts formed with inorganic and/ororganic bases. In addition, when a compound of formula I or formula IIIcontains both a basic moiety, such as, but not limited to a pyridine orimidazole, and an acidic moiety, such as, but not limited to acarboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundof formula I or formula III may be formed, for example, by reacting acompound of formula I or formula III with an amount of acid or base,such as an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

[0104] Exemplary acid addition salts include acetates, adipates,alginates, ascorbates, aspartates, benzoates, benzenesulforiates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates,hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates,lactates, maleates, methanesulfonates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates, sulfonates (such as those mentionedherein), tartarates, thiocyanates, toluenesulfonates (also known astosylates,) undecanoates, and the like. Additionally, acids which aregenerally considered suitable for the formation of pharmaceuticallyuseful salts from basic pharmaceutical compounds are discussed, forexample, by S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

[0105] Exemplary basic salts include ammonium salts, alkali metal saltssuch as sodium, lithium, and potassium salts, alkaline earth metal saltssuch as calcium and magnesium salts, salts with organic bases (forexample, organic amines) such as benzathines, dicyclohexylamines,hydrabamines (formed with N,N-bis(dehydroabietyl)ethylenediamine),N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromidesand iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, anddiamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl andstearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyland phenethyl bromides), and others.

[0106] All such acid salts and base salts are intended to bepharmaceutically acceptable salts within the scope of the invention andall acid and base salts are considered equivalent to the free forms ofthe corresponding compounds for purposes of the invention.

[0107] Compounds of formula I or formula III, and salts and solvatesthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

[0108] All stereoisomers (for example, geometric isomers, opticalisomers and the like) of the present compounds (including those of thesalts and solvates of the compounds), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention. Individualstereoisomers of the compounds of the invention may, for example, besubstantially free of other isomers, or may be admixed, for example, asracemates or with all other, or other selected, stereoisomers. Thechiral centers of the present invention can have the S or Rconfiguration as defined by the IUPAC 1974 Recommendations. The use ofthe terms “salt”, “solvate” and the like, is intended to equally applyto the salt and solvate of enantiomers, stereoisomers, rotamers,tautomers, or racemates of the inventive compounds.

[0109] When any variable (e.g., aryl, heterocycle, R₁, etc.) occurs morethan one time in any constituent or in formula I or formula III, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds.

[0110] For compounds of the invention having at least one asymmetricalcarbon atom, all isomers, including diastereomers, enantiomers androtational isomers are contemplated as being part of this invention. Theinvention includes d and I isomers in both pure form and in admixture,including racemic mixtures. Isomers can be prepared using conventionaltechniques, either by reacting optically pure or optically enrichedstarting materials or by separating isomers of a compound of formula Ior formula III.

[0111] Compounds of formula I or formula III can exist in unsolvated andsolvated forms, including hydrated forms. In general, the solvatedforms, with pharmaceutically acceptable solvents such as water, ethanoland the like, are equivalent to the unsolvated forms for purposes ofthis invention.

[0112] A compound of formula I or formula III may form pharmaceuticallyacceptable salts with organic and inorganic acids. For example,pyrido-nitrogen atoms may form salts with strong acids, while tertiaryamino groups may form salts with weaker acids. Examples of suitableacids for salt formation are hydrochloric, sulfuric, phosphoric, acetic,citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic,methanesulfonic and other mineral and carboxylic acids well known tothose skilled in the art. The salts are prepared by contacting the freebase forms with a sufficient amount of the desired acid to produce asalt in the conventional manner. The free base forms may be regeneratedby treating the salt with a suitable dilute aqueous base solution, suchas dilute aqueous sodium hydroxide, potassium carbonate, ammonia orsodium bicarbonate. The free base forms differ from their respectivesalt forms somewhat in certain physical properties, such as solubilityin polar solvents, but the salts are otherwise equivalent to theirrespective free base forms for purposes of the invention.

[0113] A further group of preferred compounds are those listed below inTable 2. TABLE 2 Example

2A

2B

2C

2D

2E

2F

2G

2H

2I

2J

[0114] as well as their pharmaceutically acceptable salts or solvates.

[0115] An even further preferred group of compounds are those listedbelow in Table 3. TABLE 3 Example

3A

3B

3C

3D

3E

3F

3G

3H

31

3J

[0116] as well as their pharmaceutically acceptable salts or solvates.

[0117] An even further group of preferred compounds are compounds fromthe group consisting of:

[0118] as well as their pharmaceutically acceptable salts or solvates.

[0119] Another aspect of this invention is a method of treating a mammal(e.g., human) having a disease or condition mediated by the neuropeptideY Y5 receptor by administering a therapeutically effective amount of acompound of formula I or formula III, or a pharmaceutically acceptablesalt of said compound to the mammal.

[0120] A dosage for the invention is about 0.001 to 30 mg/kg/day of theformula I or formula III compound. An additional dosage range is about0.001 to 3 mg/kg/day of a compound of formula I or formula III, or apharmaceutically acceptable salt of said compound.

[0121] Another aspect of this invention is directed to a method oftreating obesity comprising administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of formula Ior formula III or a pharmaceutically acceptable salt of said compound.

[0122] Another aspect of this invention is directed to a method fortreating metabolic and eating disorders such as bulimia and anorexiacomprising administering to a mammal a therapeutically effective amountof a compound of formula I or formula III, or a pharmaceuticallyacceptable salt of said compound.

[0123] Another aspect of this invention is directed to a method fortreating hyperlipidemia comprising administering to a mammal atherapeutically effective amount of a compound of formula I or formulaIII, or a pharmaceutically acceptable salt of said compound.

[0124] Another aspect of this invention is directed to a method fortreating cellulite and fat accumulation comprising administering to amammal a therapeutically effective amount of a compound of formula I orformula III, or a pharmaceutically acceptable salt of said compound.

[0125] Another aspect of this invention is directed to a method fortreating Type II diabetes comprising administering to a mammal atherapeutically effective amount of a compound of formula I or formulaIII or a pharmaceutically acceptable salt of said compound.

[0126] In addition to the “direct” effect of the compounds of thisinvention on the neuropeptide Y Y5 receptor subtype, there are diseasesand conditions that will benefit from the weight loss such as insulinresistance, impaired glucose tolerance, Type II Diabetes, hypertension,hyperlipidemia, cardiovascular disease, gall stones, certain cancers,and sleep apnea.

[0127] This invention is also directed to pharmaceutical compositions,which comprise an amount of a compound of formula I or formula III, or apharmaceutically acceptable salt of said compound and a pharmaceuticallyacceptable carrier.

[0128] This invention is also directed to pharmaceutical compositionsfor the treatment of obesity which comprise an obesity treating amountof a compound of formula I or formula III, or a pharmaceuticallyacceptable salt of said compound or of said and a pharmaceuticallyacceptable carrier therefor.

[0129] Compounds of formula I or formula III can be produced byprocesses known to those skilled in the art using either solution phaseor solid phase synthesis as shown in the following reaction schemes, inthe preparations and examples below.

[0130] Compounds of formula I where X is N, D is absent, A is absent, Eis H, R² is H, R⁴ is H, j is 1, k is 1, m is 2, n is 2, and Z is NR⁸ canbe prepared by Scheme 1, as follows:

[0131] Compounds of formula I wherein X is C, D is H, A is absent, E isH, R² is H, R⁴ is H, j is 1, k is 1, m is 2, n is 2 and Z is NR⁸ can beprepared by Scheme 4, as follows:

[0132] Combinatorial libraries of compounds of formula I can also beprepared using solid phase chemistry as shown in the schemes above.

[0133] Alternative mechanistic pathways and analogous structures withinthe scope of the invention would be apparent to those skilled in theart.

[0134] Starting materials are prepared by known methods and/or methodsdescribed in the Preparations.

[0135] The compounds of formula I or formula III exhibit Y Y5 receptorantagonizing activity, which has been correlated with pharmaceuticalactivity for treating metabolic disorders, such as obesity, eatingdisorders such as hyperphagia, and diabetes.

[0136] The compounds of formula I or formula III display pharmacologicalactivity in a test procedure designed to demonstrate Y Y5 receptorantagonist activity. The compounds are non-toxic at pharmaceuticallytherapeutic doses.

cAMP Assay

[0137] HEK-293 cells expressing the Y5 receptor subtype were maintainedin Dulbecco's modified Eagles' media (Gico-BRL) supplemented with 10%FCS (ICN), 1% penicillin-streptomycin and 200 μg/ml Geneticin®(GibcoBRL#11811-031) under a humidified 5% CO₂ atmosphere. Two days prior toassay, cells were released from T-175 tissue culture flasks using celldissociation solution (1×; non-enzymatic [Sigma #C-5914]) and seededinto 96-well, flat-bottom tissue culture plates at a density of 15,000to 20,000 cells per well. After approximately 48 hours, the cellmonolayers were rinsed with Hank's balanced salt solution (HBSS) thenpre-incubated with approximately 150 μl/well of assay buffer (HBSSsupplemented with 4 mM MgCl₂, 10 mM HEPES, 0.2% BSA [HH]) containing 1mM 3-isobutyl-1-methylxanthine ([IBMX] Sigma #1-587) with or without theantagonist compound of interest at 37° C. After 20 minutes the 1 mMIBMX-HH assay buffer (± antagonist compound) was removed and replacedwith assay buffer containing 1.5 μM (CHO cells) or 5 μM (HEK-293 cells)forskolin (Sigma #F-6886) and various concentrations of NPY in thepresence or absence of one concentration of the antagonist compound ofinterest. At the end of 10 minutes, the media were removed and the cellmonolayers treated with 75 μl ethanol. The tissue culture plates wereagitated on a platform shaker for 15 minutes, after which the plateswere transferred to a warm bath in order to evaporate the ethanol. Uponbringing all wells to dryness, the cell residues were re-solubilizedwith 250 μl FlashPlate® assay buffer. The amount of cAMP in each wellwas quantified using the [¹²⁵I]-cAMP FlashPlate® kit (NEN #SMP-001) andaccording to the protocol provided by the manufacturer. Data wereexpressed as either pmol cAMP/ml or as percent of control. All datapoints were determined in triplicate and EC₅₀'s (nM) were calculatedusing a nonlinear (sigmoidal) regression equation (GraphPad Prism™). TheK_(B) of the antagonist compound was estimated using the followingformula:

K _(B) =[B]/(1−{[A′]/[A]})

[0138] where

[0139] [A] is the EC₅₀ of the agonist (NPY) in the absence ofantagonist,

[0140] [A′] is the EC₅₀ of the agonist (NPY) in the presence ofantagonist, and

[0141] [B] is the concentration of the antagonist.

NPY Receptor Binding Assay

[0142] Human NPY Y5 receptors were expressed in CHO cells. Bindingassays were performed in 50 mM HEPES, pH 7.2, 2.5 mM CaCl₂, 1 mM MgCl₂and 0.1% BSA containing 5-10 μg of membrane protein and 0.1 nM¹²⁵L-peptide YY in a total volume of 200 μl. Non-specific binding wasdetermined in the presence of 1 μM NPY. The reaction mixtures wereincubated for 90 minutes at room temperature then filtered throughMillipore MAFC glass fiber filter plates which had been pre-soaked in0.5% polyethleneimine. The filters were washed with phosphate-bufferedsaline, and radioactivity was measured in a Packard TopCountscintillation counter.

[0143] For the compounds of this invention, a range of NPY Y5 receptorbinding activity (Ki values) of from about 0.2 nM to about 2,000 nM wasobserved. Compounds of this invention preferably have a binding activityin the range of from about 0.2 nM to about 1,000 nM, more preferablyfrom about 0.2 to about 100 nM, and most preferably from about 0.2 toabout 10 nM.

[0144] Yet another aspect of this invention are combinations of acompound of formula I or formula III, or a pharmaceutically acceptablesalt of said compound and other compounds as described below.

[0145] One such aspect of this invention is a method for treatingobesity comprising administering to a mammal (e.g., a female or malehuman)

[0146] a. an amount of a first compound, said first compound being aformula I or formula III compound, or a pharmaceutically acceptable saltof said compound; and

[0147] b. an amount of a second compound, said second compound being ananti-obesity and/or anorectic agent such as a β₃ agonist, a thyromimeticagent, an anoretic agent, or an NPY antagonist wherein the amounts ofthe first and second compounds result in a therapeutic effect.

[0148] This invention is also directed to a pharmaceutical combinationcomposition comprising: a therapeutically effective amount of acomposition comprising

[0149] a first compound, said first compound being a formula I orformula III compound, or a pharmaceutically acceptable salt of saidcompound

[0150] a second compound, said second compound being an anti-obesityand/or anorectic agent such as a β₃ agonist, a thyromimetic agent, ananoretic, or an NPY antagonist; and/or optionally a pharmaceuticalcarrier, vehicle or diluent.

[0151] Another aspect of this invention is a kit comprising:

[0152] a. an amount of a formula I or formula III compound, or apharmaceutically acceptable salt of said compound and a pharmaceuticallyacceptable carrier, vehicle or diluent in a first unit dosage form;

[0153] b. an amount of an anti-obesity and/or anorectic agent such as aβ₃ agonist, a thyromimetic agent, an anoretic agent, or an NPYantagonist and a pharmaceutically acceptable carrier, vehicle or diluentin a second unit dosage form; and

[0154] c. means for containing said first and second dosage formswherein the amounts of the first and second compounds result in atherapeutic effect.

[0155] Preferred anti-obesity and/or anorectic agents (taken singly orin any combination thereof) in the above combination methods,combination compositions and combination kits are:

[0156] phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, acholecystokinin-A (hereinafter referred to as CCK-A) agonist, amonoamine reuptake inhibitor (such as sibutramine), a sympathomimeticagent, a serotonergic agent (such as dexfenfluramine or fenfluramine), adopamine agonist (such as bromocriptine), a melanocyte-stimulatinghormone receptor agonist or mimetic, a melanocyte-stimulating hormoneanalog, a cannabinoid receptor antagonist, a melanin concentratinghormone antagonist, the OB protein (hereinafter referred to as“leptin”), a leptin analog, a leptin receptor agonist, a galaninantagonist or a GI lipase inhibitor or decreaser (such as orlistat).Other anorectic agents include bombesin agonists, dehydroepiandrosteroneor analogs thereof, glucocorticoid receptor agonists and antagonists,orexin receptor antagonists, urocortin binding protein antagonists,agonists of the glucagon-like peptide-1 receptor such as Exendin andciliary neurotrophic factors such as Axokine.

[0157] Another aspect of this invention is a method treating diabetescomprising administering to a mammal (e.g., a female or male human)

[0158] a. an amount of a first compound, said first compound being aformula I or formula III compound, or a pharmaceutically acceptable saltof said compound; and

[0159] b. an amount of a second compound, said second compound being analdose reductase inhibitor, a glycogen phosphorylase inhibitor, asorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1Binhibitor, a dipeptidyl protease inhibitor, insulin (including orallybioavailable insulin preparations), an insulin mimetic, mefformin,acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone,pioglitazone or GW-1929, a sulfonylurea, glipazide, glyburide, orchlorpropamide wherein the amounts of the first and second compoundsresult in a therapeutic effect.

[0160] This invention is also directed to a pharmaceutical combinationcomposition comprising: a therapeutically effective amount of acomposition comprising

[0161] a first compound, said first compound being a formula I orformula III compound, or a pharmaceutically acceptable salt of saidcompound;

[0162] a second compound, said second compound being an aldose reductaseinhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenaseinhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidylprotease inhibitor, insulin (including orally bioavailable insulinpreparations), an insulin mimetic, mefformin, acarbose, a PPAR-gammaligand such as troglitazone, rosaglitazone, pioglitazone, or GW-1929, asulfonylurea, glipazide, glyburide, or chlorpropamide; and optionally apharmaceutical carrier, vehicle or diluent.

[0163] Another aspect of this invention is a kit comprising:

[0164] a. an amount of a formula I or formula III compound, or apharmaceutically acceptable salt of said compound and a pharmaceuticallyacceptable carrier, vehicle or diluent in a first unit dosage form;

[0165] b. an amount of an aldose reductase inhibitor, a glycogenphosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a proteintyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor,insulin (including orally bioavailable insulin preparations), an insulinmimetic, mefformin, acarbose, a PPAR-gamma ligand such as troglitazone,rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide,glyburide, or chlorpropamide and a pharmaceutically acceptable carrier,vehicle or diluent in a second unit dosage form; and

[0166] c. means for containing said first and second dosage formswherein the amounts of the first and second compounds result in atherapeutic effect.

[0167] For preparing pharmaceutical compositions from the compoundsdescribed by this invention, inert, pharmaceutically acceptable carrierscan be either solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

[0168] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

[0169] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

[0170] Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0171] The compounds of the invention may also be deliverabletransdermally. The transdermal compositions can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

[0172] The compounds of this invention may also be deliveredsubcutaneously.

[0173] Preferably the compound is administered orally.

[0174] Preferably, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active component,e.g., an effective amount to achieve the desired purpose.

[0175] The quantity of active compound in a unit dose of preparation maybe varied or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

[0176] The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage regimen for a particularsituation is within the skill of the art. For convenience, the totaldaily dosage may be divided and administered in portions during the dayas required.

[0177] The amount and frequency of administration of the compounds ofthe invention and/or the pharmaceutically acceptable salts thereof willbe regulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two tofour divided doses.

[0178] The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures will be apparent to those skilled in the art.

[0179] Where NMR data are presented, ¹H spectra were obtained on eithera Varian VXR-200 (200 MHz, ¹H), Varian Gemini-300 (300 MHz) or XL-400(400 MHz) and are reported as ppm down field from Me₄Si with number ofprotons, multiplicities, and coupling constants in Hertz indicatedparenthetically. Where LC/MS data are presented, analyses was performedusing an Applied Biosystems API-100 mass spectrometer and ShimadzuSCL-10A LC column: Altech platinum C18, 3 micron, 33 mm×7 mm ID;gradient flow: 0 min-10% CH₃CN, 5 min-95% CH₃CN, 7 min-95% CH₃CN, 7.5min-10% CH₃CN, 9 min-stop. The retention time and observed parent ionare given.

[0180] The following constituents, solvents and reagents may be referredto by their abbreviations in parenthesis:

[0181] PTLC (preparative thin-layer chromatography);

[0182] N-Phenyltrifluoromethanesulfonimide (NPhTf₂);

[0183] trifluoromethanesulfonyloxy (TfO);

[0184] sodium triacetoxyborohydride (Na(OAc)₃BH);

[0185] sodium t-butoxide (NaOtBu);

[0186] lithium diisopropylamide (LDA);

[0187] dppp [1,3-bis(diphenylphosphino)propane];

[0188] THF (tetrahydrofuran);

[0189] DME (1,2-dimethoxyethane);

[0190] EtOAc (ethyl acetate);

[0191] Et₃N (triethylamine);

[0192] MeOH (methanol);

[0193] room temperature (r.t.);

[0194] and tert-butoxycarbonyl (Boc).

EXPERIMENTAL DETAILS EXAMPLE 1A

[0195]

[0196] Step 1. Synthesis of 14:

[0197] To a solution of 1-bromo-3,5-difluorobenzene (1.76 g, 9.14 mmol),1,4-dioxa-azaspiro(4,5)decane (1.41 g, 9.8 mmol), Pd(OAc)₂ (0.096 g,0.43 mmol), dppp (0.21 g, 0.50 mmol) in anhydrous toluene (5 ml) wasadded NaOtBu (2.04 g, 21.2 mmol). The reaction mixture was degassed withnitrogen, then sealed and heated at 90° C. for 16 hours. The mixture wasdiluted with CH₂Cl₂ (50 ml) and filtered. The filtrate was concentratedin vacuo and the residue was separated by flash column chromatography(hexane:EtOAc 100:0→95:5, v/v) to give 14 (2.0 g, 86%). MS m/e 256(M+H)⁺.

[0198] Step 2. Synthesis of 15:

[0199] To a solution of 14 (0.1 g, 0.04 mmol) in THF (4 ml) was added 5NHCl (4 ml). The reaction mixture was stirred at room temperature for 16hours. The mixture was adjusted to pH 10 with saturated sodiumbicarbonate solution and extracted with CH₂Cl₂ (2×15 ml). The combinedorganic layer was washed with brine (30 ml), separated and dried overmagnesium sulfate. The concentrated residue was separated by PTLC(hexane:EtOAc 4:1, v/v) to give 15 (0.065 g, 79%). MS m/e 212 (M+H)⁺.

[0200] Step 3. Synthesis of 16:

[0201] To a solution of 15 (0.80 g, 3.8 mmol), benzylamine (0.64 g, 6.0mmol) in DME (50 ml) was added Na(OAc)₃BH (1.6 g, 7.5 mmol). After thereaction mixture was stirred at room temperature for 16 hours, 1N NaOH(50 ml) and CH₂Cl₂ (50 ml) were added. The organic layer was separated,washed with water (50 ml) and brine (50 ml), then dried over magnesiumsulfate. The concentrated residue was dissolved in MeOH (100 ml). Formicacid (4.50 ml, 119 mmol) and 10% Pd/C (1 g, 0.9 mmol) were added. Thereaction mixture was stirred at room temperature for 16 hours. Themixture was filtered via celite. The filtrate was concentrated anddiluted with CH₂Cl₂ (50 ml) and 1N NaOH (50 ml). The organic layer waswashed with brine (50 ml), dried over magnesium sulfate, andconcentrated in vacuo to give 16 (0.66 g, 82%). MS m/e 213 (M+H)⁺.

[0202] Step 4. Synthesis of 17:

[0203] To a solution of 16 (0.21 g, 1.0 mmol) in THF (5 ml) was addedpyridine (0.25 ml, 3.0 mmol). The mixture was cooled in an icewater-bath, and N,N′-disuccinimidyl carbonate (0.28 g, 1.1 mmol) wasadded at 0° C. The mixture was stirred at room temperature for 3.5hours, then cooled in an ice water-bath, and a solution of1-tert-butoxycarbonyl-4-methylaminopiperidine, prepared via theprocedure of WO 02/22492, page 17) (0.24 g, 1.1 mmol) in THF (1 ml) wasadded at 0° C. The reaction mixture was stirred at room temperature for16 hours. The concentrated residue was diluted with CH₂Cl₂ (50 ml), thenwashed with 1N NaOH (50 ml), water (50 ml), and brine (50 ml). Theorganic layer was separated and dried over potassium carbonate. Theconcentrated residue was separated by PTLC (CH₂Cl₂:MeOH 20:1, v/v) togive 17 (0.36 g, 80%). MS m/e 453 (M+H)⁺.

[0204] Step 5. Synthesis of 18:

[0205] To a solution of 17 (0.33 g, 0.73 mmol) in CH₂Cl₂ (9 ml) wasadded trifluoroacetic acid (1 ml). The reaction mixture was stirred atroom temperature for 16 hours. The concentrated residue was diluted withCH₂Cl₂ (50 ml) and washed with 1N NaOH (50 ml). The organic layer wasseparated and dried over magnesium sulfate. The concentrated residue wasseparated by flash column chromatography (1:9 MeOH/CH₂Cl₂→1:42M ammoniain MeOH/CH₂Cl₂) to give 18 (0.22 g, 86%). MS m/e 353 (M+H)⁺.

[0206] Step 6.

[0207] To a solution of 18 (0.050 g, 0.14 mmol) in CH₂Cl₂ (2 ml) wasadded acetic anhydride (0.030 ml, 0.32 mmol) and Et₃N (0.20 ml, 1.4mmol). The reaction mixture was stirred at room temperature for 16hours. PS-Trisamine resin (100 mg) was added, and the mixture wasstirred for 16 hours. The mixture was filtered and washed with 4:1MeOH/CH₂Cl₂ (50 ml). The filtrate was concentrated and the residue wasseparated by PTLC (CH₂Cl₂: MeOH 20:1, v/v) to give 1A (0.057 g, 94%).

[0208] Reaction of 18 with propanoyl chloride by the same procedureafforded Example 1B.

EXAMPLE 1C

[0209]

[0210] To a solution of 18 (0.050 g, 0.14 mmol) and Et₃N (0.20 ml, 1.4mmol) in CH₂Cl₂ (2 ml) was added butyryl chloride (0.040 ml, 0.38 mmol)at 0° C. The reaction mixture was stirred at room temperature for 10minutes. The concentrated residue was separated by PTLC (CH₂Cl₂:MeOH10:1, v/v) to give 1C (0.058 g, 91%).

[0211] Using the procedure of Example 1C and the appropriate acidchloride, Examples 1D and 1E were prepared.

EXAMPLE 1F

[0212]

[0213] To a solution of 18 (0.050 g, 0.14 mmol) and Et₃N (0.20 ml, 1.4mmol) in CH₂Cl₂ (2 ml) was added methanesulfonyl chloride (0.040 ml,0.52 mmol) at 0° C. The reaction mixture was stirred at room temperaturefor 10 minutes. The concentrated residue was separated by PTLC(CH₂Cl₂:MeOH 10:1, v/v) to give 1F (0.052 g, 86%).

[0214] Using the same procedure, reaction of 18 with the appropriatesulfonyl chloride afforded 1G, 1H, 1I, 1J, and 1K. Example

¹H NMR MS (M + H)⁺ 1A

(CDCl₃)δ6.35(m, 2H), 6.20(m, 1H), 4.70(m, 1H), 4.42(m, 1H), 4.29(m, 1H),3.84(m, 2H), 3.61(m, 2H), 3.12 (m, 1H), 2.90(m, 2H), 2.66(s, 3H),2.55(m, 1H), 2.07(s, 3H), 2.03(m, 2H), 1.68(m, 2H), 1.48(m, 4H). 395 1B

(CDCl₃)δ6.36(m, 2H), 6.20(m, 1H), 4.76(m, 1H), 4.43(m, 1H), 4.25(m, 1H),3.88(m, 2H), 3.62(m, 2H), 3.10 (m, 1H), 2.91(m, 2H), 2.67(s, 3H),2.59(m, 1H), 2.34(q, J=7.6 Hz, 2H), 2.04(m, 2H), 1.70(m, 2H), 1.50(m,4H), 1.13(t, J=7.6 Hz, 3H). 409 1C

(CDCl₃)δ6.38(m, 2H), 6.22(m, 1H), 4.78(m, 1H), 4.42(m, 1H), 4.21 (m,1H), 3.90(m, 2H), 3.63(m, 2H), 3.10 (m, 1H), 2.91(m, 2H), 2.68(s, 3H),2.58(m, 1H), 2.31(q, J=6.8 Hz, 2H), 2.06(m, 2H), 1.78-1.58(m, 4H),1.58-1.42(m, 4H), 0.99(t, J=7.6 Hz, 3H). 423 1D

(CDCl₃)δ6.36(m, 2H), 6.21(m, 1H), 4.78(m, 1H), 4.42(m, 1H), 4.21 (m,1H), 3.98(m, 1H), 3.83(m, 1H), 3.63 (m, 2H), 3.10(m, 1H), 2.90(m, 2H),2.78(m, 1H), 2.67(s, 3H), 2.56(m, 1H), 2.06(m, 2H), 1.80-1.60(m, 2H),1.60-1.40(m, 4H), 1.11(d, J=7.2 Hz, 6H). 423 1E

(CDCl₃)δ6.34(m, 2H), 6.20(m, 1H), 4.70(m, 1H), 4.42(m, 1H), 4.27(m, 2H),3.82(m, 1H), 3.60(m, 2H), 3.18 (m, 1H), 2.90(m, 2H), 2.67(s, 3H),2.60(m, 1H), 2.04(m, 2H), 1.73(m, 2H), 1.64(m, 1H), 1.47(m, 4H), 0.95(m, 2H), 0.73(m, 2H). 421 1F

(CDCl₃)δ6.37(m, 2H), 6.20(m, 1H), 4.40(m, 1H), 4.22(m, 1H), 3.90(m, 3H),3.64(m, 2H), 2.90(m, 2H), 2.78 (s, 3H), 2.75(m, 2H), 2.71(s, 3H),2.08(m, 2H), 1.74(m, 4H), 1.50(m, 2H). 1G

(CDCl₃)δ6.34(m, 2H), 6.20(m, 1H), 4.38(m, 1H), 4.27(m, 1H), 3.90(m, 3H),3.62(m, 2H), 3-2.8(m, 6H), 2.69(s, 3H), 2.05(m, 2H), 1.69(m, 4H),1.47(m, 2H), 1.34(t, J=7.6 Hz, 3H). 445 1H

(CDCl₃)δ6.36(m, 2H), 6.21(m, 1H), 4.38(m, 1H), 4.23(m, 1H), 3.88(m, 3H),3.62(m, 2H), 3.00-2.80(m, 6H), 2.70(s, 3H), 2.04(m, 2H), 1.85(m, 2H),1.73(m, 4H), 1.48(m, 2H), 1.05 (t, J=7.6 Hz, 3H). 1I

(CDCl₃)δ6.35(m, 2H), 6.21(m, 1H), 4.40(m, 1H), 4.23(m, 1H), 3.90(m, 3H),3.62(m, 2H), 3.16(m, 1H), 2.94 (m, 4H), 2.70(s, 3H), 2.04(m, 2H),1.67(m, 4H), 1.48(m, 2H), 1.32(d, J=6.4 Hz, 6H). 1J

(CDCl₃)δ6.36(m, 2H), 6.23(m, 1H), 4.40(m, 1H), 4.22(m, 1H), 3.88 (m,3H), 3.64(m, 2H), 3.00-2.80(m, 4H), 2.71(s, 3H), 2.25(m, 1H), 2.05(m,2H), 1.73(m, 4H), 1.49(m, 2H), 1.17 (m, 2H), 0.98(m, 2H). 457 1K

(CDCl₃)δ7.75(m, 2H), 7.59(m, 1H), 7.57(m, 2H), 6.34(m, 2H), 6.20(m, 1H),4.22(m, 1H), 4.18(m, 1H), 3.88 (m, 2H), 3.80(m, 1H), 3.60(m, 2H),2.87(m, 2H), 2.66(s, 3H), 2.33(m, 2H), 1.99(m, 2H), 1.80-1.60(m, 4H),1.45(m, 2H). 493

EXAMPLE 2A

[0215]

[0216] Step 1. Synthesis of 1-Methylsulfonyl-34-piperidone

[0217] To a stirred solution of 4-piperidone hydrate hydrochloride(40.00 g, 0.260 mol) and THF (320 ml) was added CH₃SO₂Cl (31.0 ml, 0.402mol) and 15% aq. NaOH (156 ml) such that the temperature of the reactionmixture was maintained at 26-32° C. After this addition, the reactionmixture was stirred at RT for 2 hours and transferred to a separatoryfunnel. The organic layer was collected and the aqueous layer wasextracted with THF (2×250 ml). The combined organic layers were driedover Na₂SO₄. After filtration, the concentrated residuewas washed withhexane to give the product (46.0 g, 100%). ¹H NMR (CDCl₃) δ3.59 (t,J=6.00 Hz, 4H), 2.89 (s, 3H), 2.59 (t, J=5.6 Hz, 4H).

[0218] Step 2. Synthesis ofN-Methyl-1-(methylsulfonyl)-4-piperidineamine

[0219] 1-Methylsuylfonyl-4-piperidone (40.00 g, 0.226 mol), CH₃CN (240ml) and 40% CH₃NH₂ (20.4 ml, 0.263 mol) were added to a round bottomflask, and the mixture was stirred at room temperature for 1 hour. Toanother round bottom flask, NaBH(OAc)₃ (60.00 g, 0.283 mol) and 120 mlof CH₃CN were added. This solution was stirred at −10° C., to which thefirst mixture (derived from 1-methylsulfonyl-4-piperidone) was addedslowly via an additional funnel. After the addition, the reaction wasallowed to warm to room temperature and stirred overnight. The reactionmixture was concentarted to a small volume, to which 1N aq. NaOH (282ml) was added. This resulting solution was extracted with CH₂Cl₂ (3×500ml) followed by extraction with toluene until no product remained in theextraction solution. The combined organic layers were dried over Na₂SO₄.After filtration, the solution was concentrated in vacuo to give theproduct (29.0 g, 63%). ¹H NMR (CDCl₃) δ3.66 (m, 2H), 2.84 (m, 2H), 2.76(s, 3H), 2.52 (m, 1H), 2.42 (s, 3H), 1.96 (m, 2H), 1.45 (m, 2H). MS m/e193 (M+H)⁺.

[0220] Step 3. Synthesis of 19

[0221] To a solution of 4-amino-N-Boc-piperidine (3.60 g, 18.0 mmol) andpyridine (5.0 ml, 61 mmol) in THF (70 ml) in an ice-water bath was addedN,N′-disuccinimidyl carbonate (5.06 g, 19.8 mmol). The mixture wasstirred at RT for 2 hours and cooled in an ice-water bath.N-Methyl-1-(methylsulfonyl)-4-piperidineamine (3.62 g, 18.9 mmol) wasadded and the mixture was stirred at RT for 16 hours. The mixture wasdiluted with CH₂Cl₂ (300 ml) and washed with 1N NaOH (200 ml), 1N HCl(100 ml), water, and brine sequentially. The organic portion was dried(MgSO₄), concentrated, and purified by chromatography (CH₃OH:CH₂Cl₂2:100) to give 19 (4.80 g, 64%). MS m/e 419 (M+H)⁺.

[0222] Step 4. Synthesis of 20

[0223] A mixture of 19 (4.80 g, 11.5 mmol) and 4N HCl/dioxane (100 ml)in THF (100 ml) was stirred at RT for 40 hours. The mixture wasconcentrated and the residue was purified by chromatography(CH₃OH:CH₂Cl₂ 1:10 gradient to 2M NH₃/CH₃OH:CH₂Cl₂ 1:1) to give 20 (1.90g, 52%). MS m/e 319 (M+H)⁺.

[0224] Step 5.

[0225] A mixture of 20 (0.096 g, 0.30 mmol), 3-fluorophenylboronic acid(0.063 g, 0.45 mmol), copper(II) acetate (0.055 g, 0.30 mmol), andpyridine (0.048g, 0.61 mmol) in CH₂Cl₂ (2.5 ml) was stirred at RT for 17hours. The mixture was diluted with CH₂Cl₂ (20 ml) and washed with waterand aqueous sodium bicarbonate. The organic portion was dried (K₂CO₃),concentrated, and purified by PTLC (CH₃OH:CH₂Cl₂ 1:10) to give 2A(0.024g, 19%).

[0226] Using essentially the same procedure, examples 2B through 2R wereprepared. Example ¹H NMR MS (M + H)⁺ 2A

(CDCl₃)δ7.16(m, 1H), 6.69 (m, 1H), 6.60(m, 1H), 6.51(m, 1H), 4.38(m,1H), 4.25(m, 1H), 3.88 (m, 3H), 3.64(m, 2H), 2.90(m, 2H), 2.79(s, 3H),2.75(m, 2H), 2.71(s, 3H), 2.06(m, 2H), 1.74 (m, 4H), 1.53(m, 2H). 413 2B

(CDCl₃)δ7.14(m, 1H), 6.87(m, 1H), 6.78(m, 2H), 4.36(m, 1H), 4.27(m, 1H),3.86(m, 3H), 3.63 (m, 2H), 2.88(m, 2H), 2.78(s, 3H), 2.75(m, 2H),2.70(s, 3H), 2.05(m, 2H), 1.73(m, 4H), 1.51 429 2C

(CDCl₃)δ7.33(m, 1H), 7.05(m, 3H), 4.37(m, 1H), 4.27(m, 1H), 3.87(m, 3H),3.69(m, 2H), 2.91 (m, 2H), 2.78(s, 3H), 2.75(m, 2H), 2.71(s, 3H),2.09(m, 2H), 1.74(m, 4H), 1.53(m, 2H). 463 2D

(CDCl₃)δ7.30(m, 1H), 7.10(m, 3H), 4.38(m, 1H), 4.26(m, 1H), 3.88(m, 3H),3.67(m, 2H), 2.93 (m, 2H), 2.79(s, 3H), 2.76(m, 2H), 2.72(s, 3H),2.07(m, 2H), 1.74(m, 4H), 1.52(m, 2H). 420 2E

(CDCl₃)δ7.25(m, 2H), 6.94(m, 2H), 6.84(m, 1H), 4.37(m, 1H), 4.26(m, 1H),3.86(m, 3H), 3.63 (m, 2H), 2.88(m, 2H), 2.78(s, 3H), 2.75(m, 2H),2.71(s, 3H), 2.05(m, 2H), 1.75 (m, 4H), 1.56 (m, 2H). 395 2F

(CDCl₃)δ7.15(t, J=8.2 Hz, 1H), 6.54(m, 1H), 6.48(m, 1H), 6.39 (m, 1H),4.37(m, 1H), 4.26(m, 1H), 3.87(m, 3H), 3.78(s, 3H), 3.64(m, 2H), 2.91(m,2H), 2.78 (s, 3H), 2.75(m, 2H), 2.71(s, 3H), 2.04(m, 2H), 1.74(m, 4H),1.54 (m, 2H). 425 2G

(CDCl₃)δ6.76(m, 3H), 4.37(m, 1H), 4.24(m, 1H), 3.88(m, 3H), 3.63(m, 2H),2.91(m, 2H), 2.82 (s, 3H), 2.75(m, 2H), 2.71(s, 3H), 2.05(m, 2H),1.74(m, 4H), 1.48 (m, 2H). 463 2H

(CDCl₃)δ6.93(m, 4H), 4.37(m, 1H), 4.27(m, 1H), 3.87(m, 2H), 3.81(m, 1H),3.50(m, 2H), 2.84 (m, 2H), 2.78(s, 3H), 2.75(m, 2H), 2.72(s, 3H),2.05(m, 2H), 1.74(m, 4H), 1.59(m, 2H). 2I

(CDCl₃)δ7.09(m, 2H), 6.97(m, 1H), 6.88(m, 1H), 4.37(m, 1H), 4.30(m, 1H),3.87(m, 3H), 3.63 (m, 2H), 2.91(m, 2H), 2.78(s, 3H), 2.75(m, 2H),2.71(s, 3H), 2.06(m, 2H), 1.75(m, 4H), 1.58 (m, 2H). 473 2J

(CDCl₃)δ7.03(m, 1H), 6.95(m, 1H), 6.81(m, 1H), 4.37(m, 1H), 4.27(m, 1H),3.87(m, 2H), 3.81 (m, 1H), 3.52(m, 2H), 2.85(m, 2H), 2.78(s, 3H),2.75(m, 2H), 2.72(s, 3H), 2.07(m, 2H), 1.74 (m, 4H), 1.57(m, 2H). 447 2K

(CDCl₃)δ7.18(m, 2H), 6.87(m, 2H), 4.36(m, 1H), 4.28(m, 1H), 3.87(m, 3H),3.58(m, 2H), 2.86 (m, 2H), 2.77(s, 3H), 2.74(m, 2H), 2.70(s, 3H),2.05(m, 2H), 1.73(m, 4H), 1.56(m, 2H). 429 2L

(CDCl₃)δ7.32(m, 2H), 6.82(m, 2H), 4.37(m, 1H), 4.27(m, 1H), 3.85(m, 3H),3.59(m, 2H), 2.87 (m, 2H), 2.78(s, 3H), 2.74(m, 2H), 2.71(s, 3H),2.06(m, 2H), 1.73(m, 4H), 1.56(m, 2H). 473 2M

(CDCl₃)δ7.02(m, 1H), 6.74(m, 1H), 6.62(m, 1H), 4.37(m, 1H), 4.27(m, 1H),3.87(m, 2H), 3.81 (m, 1H), 3.52(m, 2H), 2.86(m, 2H), 2.78(s, 3H),2.75(m, 2H), 2.72(s, 3H), 2.08(m, 2H), 1.74 (m, 4H), 1.56(m, 2H). 431 2N

(CDCl₃)δ7.15(m, 1H), 6.74(m, 3H), 4.33(m, 2H), 3.87(m, 3H), 3.62(m, 2H),2.89(m, 2H), 2.78 (s, 3H), 2.75(m, 2H), 2.72(s, 3H), 2.31(s, 3H),2.08(m, 2H), 1.75 (m, 4H), 1.61(m, 2H). 409 2O

(CDCl₃)δ7.26(m, 1H), 7.00(m, 1H), 6.79(m, 1H), 4.37(m, 1H), 4.27(m, 1H),3.87(m, 3H), 3.60 (m, 2H), 2.90(m, 2H), 2.78(s, 3H), 2.75(m, 2H),2.71(s, 3H), 2.08(m, 2H), 1.74(m, 4H), 1.56 (m, 2H). 463 2P

(CDCl₃)δ7.72(m, 3H), 7.40(m, 1H), 7.28(m, 2H), 7.18(m, 1H), 4.34(m, 2H),3.88(m, 3H), 3.77 (m, 2H), 2.99(m, 2H), 2.78(s, 3H), 2.75(m, 2H),2.72(s, 3H), 2.13(m, 2H), 1.74(m, 4H), 1.65 (m, 2H). 445 2Q

(CDCl₃)δ7.18(m, 2H), 7.00(m, 2H), 4.35(m, 2H), 3.85(m, 3H), 3.12(m, 2H),2.80(s, 3H), 2.77 (m, 2H), 2.74(s, 3H), 2.31(s, 3H), 2.06(m, 2H),1.75(m, 4H), 1.65 (m, 2H). 409 2R

(CDCl₃)δ7.59(m, 1H), 7.44(m, 1H), 7.35(m, 1H), 7.24(m, 1H), 4.34(m, 2H),3.89(m, 3H), 3.71 (m, 2H), 2.97(m, 2H), 2.80(s, 3H), 2.76(m, 2H),2.72(s, 3H), 2.61(s, 3H), 2.10(m, 2H), 1.74 (m, 4H), 1.62(m, 2H). 437

EXAMPLE 3

[0227]

[0228] Step 1. Synthesis of 21

[0229] A mixture of 2-bromofluorobenzene (3.04 g, 17.4 mmol),1,4-dioxa-8-azaspiro(4.5)decane (2.13 g, 14.9 mmol), palladiumdibenzylideneacetone (0.657 g, 0.717 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.678 g, 1.09 mmol), andsodium t-butoxide (3.54 g, 36.8 mmol) in toluene (20 ml) was heated to95° C. for 16 hours. The mixture was diluted with CH₂Cl₂ (50 ml) andfiltered. The filtrate was evaporated and purified by columnchromatography (CH₂Cl₂ gradient to CH₃OH: CH₂Cl₂ 1:500) to give 21 (3.27g, 93%). MS m/e 238 (M+H)⁺.

[0230] Step 2. Synthesis of 22

[0231] A mixture of 21 (3.27 g, 13.8 mmol) in THF (50 ml) and aqueous 5NHCl (50 ml) was stirred at RT for 16 hours and then at 85° C. for 4hours. The volatiles were removed under reduced pressure and the residuewas partitioned between CH₂Cl₂ (2×100 ml) and aqueous ammonium hydroxide(80 ml). The combined organic portion was dried (MgSO₄), evaporated, andpurified by column chromatography (Hexanes gradient to EtOAc:Hexanes2:100) to give 22 (1.54 g, 58%). MS m/e 194 (M+H)⁺.

[0232] Step 3. Synthesis of 23

[0233] A mixture of 22 (1.54 g, 8.00 mmol), aminodiphenylmethane (1.43g, 7.48 mmol), and sodium triacetoxyborohydride (2.57 g, 12.1 mmol) indichloroethane (20 ml) was stirred at RT for 16 hours. The mixture wasdiluted with CH₂Cl₂ (80 ml) and washed with 1N NaOH (40 ml). The organicportion was dried (MgSO₄), evaporated, and purified by columnchromatography (Hexanes gradient to EtOAc:Hexanes 4:100) to give 23(2.41 g, 90%). MS m/e 361 (M+H)⁺.

[0234] Step 4. Synthesis of 24

[0235] A mixture of 23 (2.41 g, 6.70 mmol), formic acid (4.4 ml), and10% Pd/C (1.12 g) in CH₃OH (100 ml) was stirred for 3 hours. The mixturewas filtered through a celite pad and the filtrate was evaporated todryness. The residue was partitioned between CH₂Cl₂ (100 ml) and aqueousammonium hydroxide (50 ml). The organic portion was dried (MgSO₄),evaporated, and purified by column chromatography (CH₂Cl₂ gradient toCH₃OH: CH₂Cl₂ 1:4) to give 24 (1.15 g, 88%). MS m/e 195 (M+H)⁺.

[0236] Step 5

[0237] A mixture of 24 (0.087 g, 0.45 mmol), N,N′-disuccinimidylcarbonate (0.138 g, 0.538 mmol), and pyridine (0.199 g, 2.52 mmol) inTHF (7 ml) was stirred in an ice-water bath for 30 minutes and then atRT for 3 hours. N-Methyl-1-(methylsulfonyl)-4-piperidineamine (0.098 g,0.51 mmol) was added and the mixture was stirred at RT for 20 hours. Thevolatiles were removed under reduced pressure and the residue waspartitioned between aqueous ammonium chloride (15 ml) and CH₂Cl₂ (40ml). The organic portion was dried (MgSO₄), evaporated, and purified byPTLC (CH₃OH: CH₂Cl₂ 3:100) to give 3 (0.051 g, 27%). ¹H-NMR (CDCl₃)δ7.02 (m, 4H), 4.33 (m, 2H), 3.87 (m, 3H), 3.42 (m, 2H), 2.86 (m, 2H),2.78 (s, 3H), 2.75 (m, 2H), 2.73 (s, 3H), 2.08 (m, 2H), 1.74 (m, 6H). MSm/e 413 (M+H)⁺.

EXAMPLE 4A

[0238]

[0239] Step 1. Synthesis of 25

[0240] A mixture of 1-bromo-3,5-dichlorobenzene (7.43 g, 32.9 mmol),1,4-dioxa-8-azaspiro(4.5)decane (3.90 g, 27.2 mmol), palladiumdibenzylideneacetone (0.591 g, 0.645 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.598 g, 0.960 mmol), andsodium t-butoxide (4.33 g, 45.0 mmol) in toluene (30 ml) was heated to100° C. for 16 hours. The mixture was diluted with CH₂Cl₂ (20 ml) andfiltered. The filtrate was concentrated and purified by columnchromatography (Hexanes gradient to EtOAc:Hexanes 1:40) to give 25 (6.67g, 85%). MS m/e 288 (M+H)⁺.

[0241] Step 2. Synthesis of 26

[0242] A mixture of 25 (6.67 g, 23.2 mmol) in THF (20 ml) and aqueous 5NHCl (100 ml) was stirred at RT for 64 hours. The mixture was basifiedwith conc. NH₄OH and extracted with CH₂Cl₂ (3×200 ml). The combinedorganic portion was washed with brine, dried (MgSO₄), and concentratedto give 26 (5.50g, 97%). MS m/e 244 (M+H)⁺.

[0243] Step 3. Synthesis of 27

[0244] A mixture of 26 (2.44 g, 10.0 mmol), ammonium acetate (76 g, 0.99mol), and sodium cyanoborohydride (0.500 g, 7.96 mmol) in CH₃OH (200 ml)was stirred at RT for 66 hours. The mixture was concentrated and theresidue was partitioned between conc. NH₄OH (150 ml) and CH₂Cl₂ (2×150ml). The combined organic portion was washed with water (150 ml) andbrine (150 ml), dried (K₂CO₃), concentrated, and purified by columnchromatography (CH₂Cl₂ gradient to 2M NH₃/CH₃OH: CH₂Cl₂ 1:10) to give 27(1.66 g, 68%). MS m/e 245 (M+H)⁺.

[0245] Step 4. Synthesis of 28

[0246] To a solution of 27 (1.23 g, 5.02 mmol) and pyridine (3 ml) inTHF (100 ml) in an ice-water bath was added N,N′-disuccinimidylcarbonate (1.54 g, 6.03 mmol). The mixture was stirred at RT for 4 hoursand a solution of 4-methylamino-1-Boc-piperidine (1.18 g, 5.51 mmol) wasadded at 0° C. The reaction was stirred at RT for 16 hours andconcentrated. The residue was dissolved in CH₂Cl₂ (200 ml), washed with1N NaOH (150 ml) and brine, dried (K₂CO₃) and concentrated. The crudematerial and trifluoroacetic acid (8 ml) in CH₂Cl₂ (72 ml) was stirredat RT for 21 hours. The mixture was concentrated and partitioned betweenCH₂Cl₂ (200 ml) and conc. NH₄OH (50 ml). The organic portion was washedin sodium bicarbonate and brine, dried (K₂CO₃), concentrated, andpurified by column chromatography (CH₂Cl₂ gradient to 2M NH₃/CH₃OH:CH₂Cl₂ 1:10) to give 28 (1.20 g, 62%). MS m/e 385 (M+H)⁺.

[0247] Step 5.

[0248] A mixture of 28 (0.077 g, 0.20 mmol), acetic anhydride (50 μl,0.53 mmol), and triethylamine (200 μl, 1.42 mmol) in CH₂Cl₂ (5 ml) wasstirred at RT for 3 hours. 1N NaOH (2 ml) was added and the organicportion was dried (MgSO₄), concentrated, and purified by PTLC (CH₃OH:CH₂Cl₂ 1:10) to give 4A (0.080 g, 94%).

[0249] Using essentially the same procedure, 4B was prepared.

EXAMPLE 4C

[0250]

[0251] A mixture of 28 (0.077 g, 0.20 mmol), isobutyryl chloride (45 μl,0.43 mmol), and triethylamine (200 μl, 1.42 mmol) in CH₂Cl₂ (5 ml) wasstirred at RT for 2 hours. The mixture was washed with 1N NaOH (2 ml),dried (MgSO₄), concentrated, and purified by PTLC (CH₃OH: CH₂Cl₂ 1:10)to give 4C (0.085 g, 93%).

[0252] Using essentially the same procedure, 4D, 4E, 4F, 4G, and 4H wereprepared.

EXAMPLE 4I

[0253]

[0254] A mixture of 28 (0.077 g, 0.20 mmol), ethanesulfonyl chloride (45μl, 0.47 mmol), and triethylamine (200 μl, 1.42 mmol) in CH₂Cl₂ (5 ml)was stirred at RT for 2 hours. The mixture was washed with 1N NaOH,dried (MgSO₄), concentrated, and purified by PTLC (CH₃OH: CH₂Cl₂ 1:10)to give 4I (0.082 g, 86%).

[0255] Using essentially the same procedure, 4J, 4K, and 4L wereprepared. Example ¹H NMR MS (M + H)⁺ 4A

(CDCl₃)δ6.77(m, 3H), 4.74(m, 1H), 4.44(m, 1H), 4.21(m, 1H), 3.86(m, 2H),3.63(m, 2H), 3.15 (m, 1H), 2.93(m, 2H), 2.68(s, 3H), 2.58(m, 1H),2.11(s, 3H), 2.08(m, 2H), 1.68(m, 2H), 1.53(m, 4H). 427 4B

(CDCl₃)δ6.75(m, 3H), 4.75(m, 1H), 4.43(m, 1H), 4.22(m, 1H), 3.89(m, 2H),3.63(m, 2H), 3.09 (m, 1H), 2.92(m, 2H), 2.68(s, 3H), 2.58(m, 1H),2.35(q, J=7.4Hz, 2H), 2.05(m, 2H), 1.69(m, 2H), 1.49(m, 4H), 1.15(t,J=7.4Hz, 3H). 441 4C

(CDCl₃)δ6.75(m, 3H), 4.75(m, 1H), 4.44(m, 1H), 4.22(m, 1H), 4.00(m, 1H),3.86(m, 1H), 3.63 (m, 2H), 3.11(m, 1H), 2.92(m, 2H), 2.80(m, 1H),2.68(s, 3H), 2.56(m, 1H), 2.06(m, 2H), 1.71(m, 2H), 1.49(m, 4H), 1.12(m,6H). 455 4D

(CDCl₃)δ6.74(m, 3H), 4.74(m, 1H), 4.43(m, 1H), 4.24(m, 1H), 3.89(m, 2H),3.63(m, 2H), 3.09 (m, 1H), 2.92(m, 2H), 2.66(s, 3H), 2.56(m, 1H),2.31(m, 2H), 2.06 (m, 2H), 1.69(m, 4H), 1.47(m, 4H), 0.96(t, J=7.2 Hz,3H). 455 4E

(CDCl₃)δ6.75(m, 3H), 4.72(m, 1H), 4.46(m, 1H), 4.28(m, 1H), 4.22(m, 1H),3.89(m, 1H), 3.63 (m, 2H), 3.16(m, 1H), 2.92(m, 2H), 2.68(s, 3H),2.62(m, 1H), 2.06(m, 2H), 1.42-1.78(m, 7H), 0.97(m, 2H), 0.75(m, 2H). 4F

(CDCl₃)δ6.72(m, 3H), 4.69(m, 1H), 4.41(m, 1H), 4.27(m, 1H), 3.84(m, 1H),3.74(m, 1H), 3.62 (m, 2H), 3.24(m, 1H), 2.83-3.05 (m, 4H), 2.65(s, 3H),2.56(m, 1H), 2.34(m, 2H), 1.74-2.20(m, 5H), 1.65(m, 2H), 1.46(m, 4H).467 4G

(CDCl₃)δ7.46(m, 1H), 7.30(m, 1H), 7.05(m, 1H), 6.78(m, 3H), 4.55(m, 3H),4.24(m, 1H), 3.87 (m, 1H), 3.64(m, 2H), 2.97(m, 4H), 2.71(s, 3H),2.08(m, 2H), 1.37-1.78(m, 6H). 4H

(CDCl₃)δ8.66(m, 2H), 7.77(m, 1H), 7.37(m, 1H), 6.75(m, 3H), 4.81(m, 1H),4.51(m, 1H), 4.25 (m, 1H), 3.84(m, 2H), 3.63(m, 2H), 3.18(m, 1H),2.89(m, 3H), 2.71(s, 3H), 2.05(m, 2H), 1.4-2.0(m, 6H). 490 4I

(CDCl₃)δ6.74(m, 3H), 4.37(m, 1H), 4.23(m, 1H), 3.88(m, 3H), 3.64(m, 2H),2.95(m, 5H), 2.71(s, 3H), 2.05(m, 2H), 1.71(m, 5H), 1.49(m, 2H), 1.36(t,J=7.4Hz, 3H). 477 4J

(CDCl₃)δ6.74(m, 3H), 4.37(m, 1H), 4.25(m, 1H), 3.87(m, 3H), 3.63(m, 2H),2.87(m, 5H), 2.71(s, 3H), 2.05(m, 2H), 1.83(m, 2H), 1.69(m, 5H), 1.49(m,2H), 1.05(t, J=7.8Hz, 3H). 491 4K

(CDCl₃)δ6.74(m, 3H), 4.39(m, 1H), 4.24(m, 1H), 3.90(m, 3H), 3.61(m, 2H),3.16(m, 1H), 2.93 (m, 4H), 2.71(s, 3H), 2.05(m, 2H), 1.68(m, 4H),1.49(m, 2H), 1.33(d, J=6.4Hz, 6H). 4L

(CDCl₃)δ7.77(m, 2H), 7.56(m, 3H), 6.74(m, 3H), 4.18(m, 2H), 3.84(m, 3H),3.62(m, 2H), 2.92 (m, 2H), 2.68(s, 3H), 2.36(m, 2H), 2.03(m, 2H),1.69(m, 4H), 1.47 (m, 2H). 525

EXAMPLE 5A

[0256]

[0257] Step 1. Synthesis of 29 and 30:

[0258] A mixture of 4-phenylcyclohexanone (1.7 g, 10 mmol) andbenzhydrylamine (2.0 g, 11 mmol) in DME (60 ml) was stirred at roomtemperature for 2 hours. Then Na(OAc)₃BH (3.2 g, 15 mmol) was added.After the reaction mixture was stirred at room temperature for 2 days,1N NaOH (100 ml) was added. The solution was extracted with CH₂Cl₂(3×100 ml). The combined organic layer was separated and dried overpotassium carbonate. The concentrated residue was separated by flashcolumn chromatography (CH₂Cl₂:hexane 1:9→100:0, v/v) to give 29 (2.13 g)and 30 (0.68 g), total yield being 82%. MS m/e 342 (M+H)⁺.

[0259] Step 2. Synthesis of 31:

[0260] To a solution of 29 (1.9 g, 5.6 mmol) in MeOH (100 ml) was addedformic acid (4.50 ml, 119 mmol) and 10% Pd/C (1.9 g. 1.8 mmol). Thereaction mixture was stirred at room temperature for 16 hours. It wasfiltered via celite and the celite was washed with 2M ammonia/MeOH. Thefiltrate was concentrated, then diluted with CH₂Cl₂ (100 ml), and washedwith water (50 ml). The aqueous layer was adjusted to pH 11 with ammoniahydroxide solution, then extracted with CH₂Cl₂ (3×100 ml). The combinedorganic layer was separated, dried over magnesium sulfate andconcentrated to give 31 (0.90 g, 92%). MS m/e 176 (M+H)⁺.

[0261] Step 3. Synthesis of 32:

[0262] To a solution of 31 (0.90 g, 5.1 mmol) in THF (80 ml) was addedpyridine (2.0 ml, 24 mmol). The mixture was cooled in an ice water-bath,and N,N′-disuccinimidyl carbonate (1.45 g, 5.66 mmol) was added at 0° C.The mixture was stirred at room temperature for 3.5 hours and cooled to0° C., 1-tert-butoxycarbonyl-4-methylaminopiperidine (1.15 g, 5.37 mmol)was added. The reaction mixture was stirred at room temperature for 16hours. The mixture was concentrated to give crude 32 (2.1 g, 96%). MSm/e 416 (M+H)⁺.

[0263] Step 4. Synthesis of 33:

[0264] A solution of 32 (2.05 g, 4.94 mmol) in 4N HCl/1,4-dioxane (100ml) was stirred at room temperature for 5 hours. The concentratedresidue was washed with ether to give 33 (1.83 g, 100%). MS m/e 316(M+H)⁺.

[0265] Step 5.

[0266] To a solution of 33 (0.07 g, 0.2 mmol) and Et₃N (0.20 ml, 1.4mmol) in CH₂Cl₂ (2 ml) was added acetic anhydride (0.040 ml, 0.43 mmol)at 0° C. and the reaction mixture was stirred for another 1 hour at 0°C. The concentrated residue was separated by PTLC (CH₂Cl₂: MeOH 20:1,v/v) to give 5A (0.055g, 77%).

[0267] Using essentially the same procedure, 5B was prepared.

EXAMPLE 5C

[0268]

[0269] To a solution of 33 (0.07 g, 0.2 mmol) and Et₃N (0.20 ml, 1.4mmol) in CH₂Cl₂ (2 ml) was added butyryl chloride (0.040 ml, 0.38 mmol)at 0° C. The reaction mixture was stirred at room temperature for 30minutes. PS-Trisamine resin (100 mg) was added and the mixture wasstirred for another 2 hours, then filtered. The filtrate wasconcentrated and the residue was separated by PTLC (CH₂Cl₂: MeOH 20:1,v/v) to give 5C (0.055 g, 71%).

[0270] Using essentially the same procedure, 5D and 5E were prepared.

EXAMPLE 5F

[0271]

[0272] To a solution of 33 (0.07 g, 0.2 mmol) and Et₃N (0.20 ml, 1.4mmol) in CH₂Cl₂ (2 ml) was added methanesulfonyl chloride (0.040 ml,0.52 mmol) at 0° C. The reaction mixture was stirred at room temperaturefor 1 hour. PS-Trisamine (100 mg) was added and the mixture was stirredfor another hour. It was filtered and the filtrate was concentrated. Theresidue was separated by PTLC (CH₂Cl₂: MeOH 20:1, v/v) to give 5F (0.046g, 59%).

[0273] Using essentially the same procedure, Examples 5G, 5H, 5I, and 5Jwere prepared. Example

¹H NMR MS (M + H) 5A

-(CDCl₃)δ7.31(m, 2H), 7.20(m, 3H), 4.72(m, 1H), 4.58(m, 1H), 4.48(m,1H), 4.10(m, 1H), 3.85(m, 1H), 3.18 (m, 1H), 2.73(s, 3H), 2.60(m, 2H),2.09(s, 3H), 1.90-1.44(m, 11H). 358 5B

-(CDCl₃)δ7.31(m, 2H), 7.20(m, 3H), 4.75(m, 1H), 4.58(m, 1H), 4.48(m,1H), 4.08(m, 1H), 3.90(m, 1H), 3.10 (m, 1H), 2.72(s, 3H), 2.60(m, 2H),2.36(m, 2H), 1.90-1.40(m, 11H), 1.12(m, 3H). 5C

-(CDCl₃)δ7.31(m, 2H), 7.20(m, 3H), 4.78(m, 1H), 4.58(m, 1H), 4.42(m,1H), 4.08(m, 1H), 3.90(m, 1H), 3.10 (m, 1H), 2.72(s, 3H), 2.60(m, 2H),2.30(m, 2H), 1.95-1.40(m, 13H), 0.96(t, J=7.6 Hz, 3H). 386 5D

-(CDCl₃)δ7.31(m, 2H), 7.20(m, 3H), 4.78(m, 1H), 4.54(m, 1H), 4.45(m,1H),4.08(m, 1H), 3.98(m, 1H),3.10 (m, 1H), 2.80(m, 1H), 2.73(s, 3H),2.60(m, 2H), 1.98-1.40(m, 11H), 1.11(dd, J=6.8 Hz, J=12 Hz, 6H). 386 5E

-(CDCl₃)δ7.29(m, 2H), 7.21(m, 3H), 4.70(m, 1H), 4.50(m, 2H), 4.28(m,1H), 4.10(m, 1H), 3.18(m, 1H), 2.74 (s, 3H), 2.81(m, 2H), 1.98-1.42(m,12H), 0.97(m, 2H), 0.75(m, 2H). 384 5F

-(CDCl₃)δ7.32(m, 2H), 7.22(m, 3H), 4.57(m, 1H), 4.40(m, 1H), 4.08(m,1H), 3.88(m, 2H), 2.80-2.65(m, 8H), 2.60(m, 1H), 1.90-1.52(m, 11H). 3945G

-(CDCl₃)δ7.30(m, 2H), 7.21(m, 3H), 4.58(m, 1H), 4.40(m, 1H), 4.05(m,1H), 3.90(m, 2H), 2.94(m, 3H), 2.86 (m, 1H), 2.76(s, 3H), 2.60(m, 1H),1.98-1.50(m, 11H), 1.34(t, J=7.6 Hz, 3H). 408 5H

-(CD₃OD)δ6.93(m, 4H), 6.82(m, 1H), 3.88(m, 1H), 3.60(m, 1H), 3.48 (m,2H), 2.97(m, 1H), 2.65(m, 2H), 2.55(m, 2H), 2.47(s, 3H), 2.30(m, 1H),1.60-1.20(m, 13H), 0.72(t, J=7.2 Hz, 3H). 422 5I

-(CD₃OD)δ7.26(m, 4H), 7.18(m, 1H), 4.22(m, 1H), 4.00-3.80(m, 3H),3.30(m, 2H), 298(m, 2H), 2.80(s, 3H), 2.62(m, 1H), 1.98-1.58(m, 11H),1.30(d, J=7.2 Hz, 6H). 422 5J

-(CD₃OD)δ7.29(m, 2H), 7.21(m, 3H), 4.78(m, 1H), 4.40(m, 1H), 4.08(m,1H), 3.85(m, 2H), 2.88(m, 2H), 2.77 (s, 3H), 2.60(m, 1H), 2.26(m, 1H),1.98-1.50(m, 11H), 1.16(m, 2H), 0.98(m, 2H). 420

EXAMPLE 6A

[0274]

[0275] Step 1. Synthesis of 34

[0276] A mixture of 30 (2.0 g, 5.8 mmol) and 10% Pd/C (2.0 g) in 4.4%HCOOH/MeOH (100 ml) was stirred at room temperature for 16 hours. Themixture was filtered through a pad of celite and the pad was washed withMeOH. The filtrate was concentrated and the residue was purified bycolumn chromatography (gradient of CH₂Cl₂ to 1:9 MeOH/CH₂Cl₂ to 1:5 2MNH₃/MeOH in CH₂Cl₂) to give 34 (0.86 g, 84%). MS m/e 176 (M+H)⁺.

[0277] Step 2. Synthesis of 35

[0278] To an ice-cold solution of 34 (0.86 g, 4.9 mmol) and pyridine(2.0 ml, 24 mmol) in THF (60 ml) was added N,N′-disuccinimidylcarbonate(1.38 g, 5.39 mmol). The mixture was stirred at room temperature for 3hours and then cooled in an ice-water bath.1-tert-Butoxycarbonyl-4-methylaminopiperidine (1.10 g, 5.14 mmol) wasadded and the mixture was stirred at room temperature for 16 hours. Thereaction mixture was evaporated to dryness and the residue waspartitioned between CH₂Cl₂ (200 ml) and 1N NaOH (100 ml). The organiclayer was washed with water and brine, dried over MgSO₄, andconcentrated. The crude product was purified by column chromatography(CH₂Cl₂, then 2:98 MeOH/CH₂Cl₂) to give 35 (1.8 g, 88%). MS m/e 10 416(M+H)⁺.

[0279] Step 3. Synthesis of 36

[0280] A solution of 35 (1.7 g, 4.1 mmol) in 4N HCl/1,4-dioxane (150 ml)was stirred at room temperature for 3 hours. The concentrated residuewas triturated with ether to give 36 (1.38 g, 95%). MS m/e 316 (M+H)⁺.

[0281] Step 4

[0282] A solution of 36 (70 mg, 0.22 mmol), acetic anhydride (40 μl,0.43 mmol), and Et₃N (200 μl, 1.43 mmol) in CH₂Cl₂ (2.5 ml) was stirredat room temperature for 1 hour. The concentrated residue was purified byPTLC (20:1 CH₂Cl₂/MeOH) to give 6A (60 mg, 76%).

[0283] Using essentially the same procedure, 6B was prepared.

EXAMPLE 6C

[0284]

[0285] To a solution of 36 (70 mg, 0.22 mmol) and Et₃N (200 μl, 1.43mmol) in CH₂Cl₂ (2.5 ml) in an ice-water bath was added butyryl chloride(40 μl, 0.38 mmol). The mixture was warmed to room temperature andstirred for 1 hour. PS-Trisamine resin (100 mg) was added and themixture was stirred for another 2 hours, then filtered. The filtrate wasconcentrated and the residue was purified by PTLC (10:1 CH₂Cl₂/MeOH) togive 6C (60 mg, 71%).

[0286] Using essentially the same procedure, 6D and 6E were prepared.

EXAMPLE 6F

[0287]

[0288] To a solution of 36 (70 mg, 0.22 mmol) and Et₃N (200 μl, 1.43mmol) in CH₂Cl₂ (2.5 ml) in an ice-water bath was added methanesulfonylchloride (40 μl, 0.52 mmol). The mixture was stirred at room temperaturefor 1 hour. PS-Trisamine (100 mg) was added and the mixture was stirredfor 2 hours, then filtered. The filtrate was concentrated and theresidue was purified by PTLC (10:1 CH₂Cl₂/MeOH) to give 6F (35 mg, 40%).

[0289] Using essentially the same procedure, examples 6G, 6H, 6I, and 6Jwere prepared. Example

¹H NMR MS (M + H) 6A

(CDCl₃)δ7.18-7.31(m, 5H), 4.73(m, 1H), 4.47(m, 1H), 4.20(m, 1H), 3.87(m, 1H), 3.74(m, 1H), 3.15(m, 1H), 2.69(s, 3H), 2.59(m, 1H), 2.48(m,1H), 2.14(m, 2H), 2.10(s, 3H), 1.94 (m, 2H), 1.4-1.8(m, 6H), 1.27(m,2H). 358 6B

(CDCl₃)δ7.16-7.29(m, 5H), 4.73(m, 1H), 4.45(m, 1H), 4.23(m, 1H), 3.89(m, 1H), 3.70(m, 1H), 3.07(m, 1H), 2.67(s, 3H), 2.4-2.6(m, 2H), 2.37 (m,2H), 2.13(m, 2H), 1.92(m, 2H), 1.4-1.8(m, 6H), 1.26(m, 2H), 1.13 (m,3H). 372 6C

(CDCl₃)δ7.16-7.29(m, 5H), 4.73(m, 1H), 4.42(m, 1H), 4.22(m, 1H), 3.90(m, 1H), 3.69(m, 1H), 3.06(m, 1H), 2.67(s, 3H), 2.4-2.6(m, 2H), 2.30 (m,2H), 2.13(m, 2H), 1.90(m, 2H), 1.4-1.8(m, 8H), 1.22(m, 2H), 0.95 (m,3H). 386 6D

(CDCl₃)δ7.17-7.26(m, 5H), 4.73(m, 1H), 4.43(m, 1H), 4.22(m, 1H), 3.97(m, 1H), 3.70(m, 1H), 3.06(m, 1H), 2.78(m, 1H), 2.67(s, 3H), 2.4-2.6 (m,2H), 2.12(m, 2H), 1.90(m, 2H), 1.4-1.8(m, 6H), 1.24(m, 2H), 1.10 (m,6H). 386 6E

(CDCl₃)δ7.18-7.27(m, 5H), 4.70(m, 1H), 4.46(m, 1H), 4.27(m, 2H). 3.71(m, 1H), 3.14(m, 1H), 2.68(m, 3H), 2.61(m, 1H), 2.45(m, 1H), 2.13(m,2H), 1.92(m, 2H), 1.4-1.8(m, 7H), 1.24(m, 2H), 0.97(m, 2H), 0.73(m, 2H).384 6F

(CDCl₃)δ7.18-7.28(m, 5H), 4.40(m, 1H), 4.21(m, 1H), 3.87(m, 2H), 3.69(m, 1H), 2.6-2.8(m, 8H), 2.46(m, 1H), 2.14(m, 2H), 1.93(m, 2H), 1.74 (m,4H), 1.61(m, 2H), 1.26(m, 2H). 394 6G

(CDCl₃)δ7.18-7.28(m, 5H), 4.39(m, 1H), 4.22(m, 1H), 3.88(m, 2H), 3.65(m, 1H), 2.95(m, 2H), 2.86(m, 2H), 2.70(s, 3H), 2.46(m, 1H), 2.13(m,2H), 1.92(m, 2H), 1.5-1.8(m, 6H), 1.2-1.4(m, 5H). 6H

(CDCl₃)δ7.18-7.28(m, 5H), 4.39(m, 1H), 4.21(m, 1H), 3.88(m, 2H), 3.72(m, 1H), 2.88(m, 4H), 2.71(s, 3H), 2.46(m, 1H), 2.14(m, 2H), 1.5-2.0 (m,10H), 1.26(m, 2H), 1.04(m, 3H). 422 6I

(CDCl₃)δ7.19-7.28(m, 5H), 4.41(m, 1H), 4.21(m, 1H), 3.91(m, 2H), 3.72(m, 1H), 3.17(m, 1H), 2.96(m, 2H), 2.71(s, 3H), 2.47(m, 1H), 2.14(m,2H), 1.93(m, 2H), 1.5-1.8(m, 6H), 1.33(d, J=6.8 Hz, 6H), 1.26(m, 2H).422 6J

(CDCl₃)δ7.16-7.30(m, 5H), 4.37(m, 1H), 4.24(m, 1H), 3.87(m, 2H), 3.71(m, 1H), 2.89(m, 2H), 2.71(s, 3H), 2.47(m, 1H), 2.25(m, 1H), 2.13(m,2H), 1.93(m, 2H), 1.5-1.8(m, 6H), 1.28(m, 2H), 1.15(m, 2H), 0.98(m, 2H).420

EXAMPLE 7A

[0290]

[0291] Step 1. Synthesis of 37

[0292] To a solution of diisopropylamine (3.75 g, 37.1 mmol) in THF (20ml) in dry ice-acetone bath was added 2.5 M butyllithium in hexanes(14.4 ml). The mixture was stirred for 10 min and a solution of1,4-dioxa-spiro[4,5]decan-8-one (5.00 g, 32.0 mmol) in THF (25 ml) wasadded. After 1 hour, N-phenyltrifluoromethanesulfonimide (11.5 g, 32.3mmol) in THF (25 ml) was added and the mixture was kept in an ice-waterbath. The reaction was allowed to warm to RT slowly and stirred for 16hours. The volatiles were removed under reduced pressure and the residuewas purified by column chromatography (Hexanes gradient to EtOAc:Hexanes9:1000) to give 37 (6.86 g, 74%). ¹H-NMR (CDCl₃) 5.66 (m, 1H), 3.99 (m,4H), 2.54 (m, 2H), 2.41 (m, 2H), 1.90 (m, 2H).

[0293] Step 2. Synthesis of 38

[0294] A mixture of 37 (4.33 g, 15.0 mmol), 3,5-difluorophenyl boronicacid (3.63 g, 23.0 mmol), lithium chloride (2.60 g, 61.3 mmol), sodiumcarbonate (6.44 g, 60.8 mmol), and palladiumtetrakis(triphenylphosphine) (1.30 g, 1.13 mmol) in DME (50 ml) andwater (27 ml) was refluxed under nitrogen for 5 hours. The mixture wascooled down to RT and partitioned between CH₂Cl₂ (300 ml) and 2N sodiumcarbonate (200 ml). The aqueous layer was extracted with CH₂Cl₂ (200 ml)and the combined organic portion was dried, concentrated, and purifiedby column chromatography (Hexanes gradient to EtOAc:Hexanes 1:40) togive 38 (2.90 g, 90%). ¹H-NMR (CDCl₃) δ6.87 (m, 2H), 6.65 (m, 1H), 6.04(m, 1H), 4.02 (s, 4H), 2.59 (m, 2H), 2.46 (m, 2H), 1.90 (m, 2H).

[0295] Step 3. Synthesis of 39

[0296] A mixture of 38 (0.692 g, 2.75 mmol) and 10% Pd/C (0.100 g) inCH₃OH (30 ml) was stirred under 1 atm hydrogen for 4 hours. The mixturewas filtered and concentrated to give 39 (0.650 g, 93%). MS m/e 255(M+H)⁺.

[0297] Step 4. Synthesis of 40

[0298] A solution of 39 (3.50 g, 13.8 mmol) in THF (60 ml) and 5N HCl(60 ml) was refluxed for 4 hours. The volatiles were removed underreduced pressure and the residue was partitioned between CH₂Cl₂ andsodium carbonate. The organic portion was dried (MgSO₄), concentrated,and purified by column chromatography (Hexanes gradient to EtOAc:Hexanes1:10) to give 40 (2.00 g, 66%). ¹H-NMR (CDCl₃) δ6.78 (m, 2H), 6.66 (m,1H), 3.02 (m, 1H), 2.52 (m, 4H), 2.21 (m, 2H), 1.90 (m, 2H).

[0299] Step 5. Synthesis of 41

[0300] A mixture of the 40 (2.00 g, 9.52 mmol), diphenylmethylamine(2.09 g, 11.4 mmol), and sodium triacetoxyborohydride (2.40 g, 11.3mmol) in dichloroethane (100 ml) was stirred for 16 hours. The mixturewas diluted with CH₂Cl₂ (100 ml) and washed with 1N NaOH (100 ml). Theorganic portion was passed through a pad of silica, concentrated, andpurified by column chromatography (Hexanes gradient to EtOAc:Hexanes1:50) to give 41 (0.660 g, 18%). MS m/e 378 (M+H)⁺.

[0301] Step 6. Synthesis of 42

[0302] A mixture of 41 (0.640 g, 1.70 mmol), ammonium formate (1.90 g,30.1 mmol), and 10% Pd/C (0.130 g) in CH₃OH (30 ml) was stirred at RTfor 1 hour. The mixture was filtered through a pad of celite andconcentrated. The residue was partitioned between CH₂Cl₂ (150 ml) andconc. NH₄OH (50 ml). The organic portion was dried (K₂CO₃),concentrated, and purified by column chromatography (CH₂Cl₂ gradient to2M NH₃/CH₃OH:CH₂Cl₂ 1:10) to give 42 (0.250 g, 70%). MS m/e 212 (M+H)⁺.

[0303] Step 7. Synthesis of 43

[0304] To a solution of 42 (0.250 g, 1.18 mmol) and pyridine (1.0 ml, 12mmol) in an ice-water bath was added N,N′-disuccinimidyl carbonate(0.362 g, 1.42 mmol). The mixture was stirred at RT for 2.5 hours andcooled in an ice-water bath. A solution of4-methylamino-1-Boc-piperidine (0.278 g, 1.30 mmol) was added and themixture was stirred at RT for 16 hours. The volatiles were removed underreduced pressure and the residue was partitioned between CH₂Cl₂ (100 ml)and 1N NaOH (50 ml). The organic portion was washed with 1N HCl, brine,dried (K₂CO₃), and concentrated. The resulting solid was taken up inCH₂Cl₂ (25 ml) and 4N HCl/dioxane (25 ml) and the solution was stirredat RT for 2.5 hours. The mixture was concentrated and the residue waspartitioned between CH₂Cl₂ (150 ml) and conc. NH₄OH (50 ml). The organicportion was dried (K₂CO₃), concentrated, and purified by columnchromatography (CH₂Cl₂ gradient to 2M NH₃/CH₃OH:CH₂Cl₂ 1:10) to give 43(0.43 g, 96%). MS m/e 352 (M+H)⁺.

[0305] Step 8

[0306] A solution of 43 (0.058 g, 0.15 mmol), acetic anhydride (40 μl,0.42 mmol), and triethylamine (200 μl, 1.42 mmol) in CH₂Cl₂ (2 ml) wasstirred at RT for 2 hours. 1N NaOH (2 ml) was added and the organicportion was washed with brine, dried (MgSO₄), concentrated, and purifiedby PTLC (CH₃OH: CH₂Cl₂ 1:20) to give 7A (0.036 g, 61%).

[0307] Using essentially the same procedure, 7B was prepared.

EXAMPLE 7C

[0308]

[0309] A solution of 43 (0.058 g, 0.15 mmol), isobutyryl chloride (40μl, 0.38 mmol), and triethylamine (200 μl, 1.42 mmol) in CH₂Cl₂ (2 ml)was stirred at RT for 16 hours. The mixture was diluted with CH₂Cl₂ (5ml) and washed with 1N NaOH (2 ml). The organic portion was dried(MgSO₄), concentrated, and purified by PTLC (CH₃OH: CH₂Cl₂ 1:20) to give7C (0.041 g, 65%).

[0310] Using essentially the same procedure, 7D and 7E were prepared.

EXAMPLE 7F

[0311]

[0312] A solution of 43 (0.058 g, 0.15 mmol), methanesulfonyl chloride(40 μl, 0.52 mmol), and triethylamine (200 μl, 1.42 mmol) in CH₂Cl₂ (2ml) was stirred at RT for 16 hours. The mixture was diluted with CH₂Cl₂(5 ml) and washed with 1N NaOH (2 ml). The organic portion was dried(MgSO₄), concentrated, and purified by PTLC (CH₃OH: CH₂Cl₂ 1:20) to give7F (0.030 g, 47%).

[0313] Using essentially the same procedure, 7G, 7H, 7I, and 7J wereprepared. Example ¹H NMR MS(M + H)⁺ 7A

δ(CDCl₃)δ6.71(m, 2H), 6.61(m, 1H), 4.72(m, 1H), 4.46(m, 1H), 4.22(m,1H), 3.86(m, 1H), 3.69(m, 1H), 3.14(m, 1H), 2.68(s, 3H), 2.58 (m, 1H),2.46(m, 1H), 2.12(m, 2H), 2.09(s, 3H), 1.92(m, 2H), 1.68(m, 2H), 1.52(m,4H), 1.25(m, 2H). 394 7B

δ(CDCl₃)δ6.71(m, 2H), 6.62(m, 1H), 4.75(m, 1H), 4.46(m, 1H), 4.18(m,1H), 3.91(m, 1H), 3.71(m, 1H), 3.09(m, 1H), 2.68(s, 3H), 2.59 (m, 1H),2.47(m, 1H), 2.34(m, 2H), 2.15(m, 2H), 1.93(m, 2H), 1.4-1.8 (m, 6H),1.27(m, 2H), 1.15(t, J=7.8 Hz, 3H). 408 7C

δ(CDCl₃)δ6.71(m, 2H), 6.58(m, 1H), 4.74(m, 1H), 4.44(m, 1H), 4.21(m,1H), 3.97(m, 1H), 3.69(m, 1H), 3.09(m, 1H), 2.78(m, 1H), 2.66(s, 3H),2.56(m, 1H), 2.44(m, 1H), 2.14(m, 2H), 1.93(m, 2H), 1.4-1.8(m, 6H),1.25(m, 2H), 1.10(m, 6H). 422 7D

δ(CDCl₃)δ6.71(m, 2H), 6.62(m, 1H), 4.75(m, 1H), 4.46(m, 1H), 4.18(m,1H), 3.91(m, 1H), 3.71(m, 1H), 3.11(m, 1H), 2.68(s, 3H), 2.58 (m, 1H),2.46(m, 1H), 2.31(m, 2H), 2.16(m, 2H), 1.93(m, 2H), 1.4-1.8 (m, 8H),1.27(m, 2H), 0.97(t, J=7.6 Hz, 3H). 422 7E

δ(CDCl₃)δ6.72(m, 2H), 6.62(m, 1H), 4.71(m, 1H), 4.49(m, 1H), 4.28(m,1H), 4.19(m, 1H), 3.72(m, 1H), 3.16(m, 1H), 2.69(s, 3H), 2.62 (m, 1H),2.47(m, 1H), 2.16(m, 2H), 1.93(m, 2H), 1.4-1.8(m, 7H), 1.27 (m, 2H),0.98(m, 2H), 0.75(m, 2H). 420 7F

δ(CDCl₃)δ6.72(m, 2H), 6.62(m, 1H), 4.39(m, 1H), 4.21(m, 1H), 3.89(m,2H), 3.71(m, 1H), 2.78(s, 3H), 2.75(m, 2H), 2.71(s, 3H), 2.46 (m, 1H),2.15(m, 2H), 1.93(m, 2H), 1.72(m, 4H), 1.56(m, 2H), 1.27(m, 2H). 430 7G

δ(CDCl₃)δ6.72(m, 2H), 6.62(m, 1H), 4.40(m, 1H), 4.18(m, 1H), 3.90 (m,2H), 3.69(m, 1H), 2.96(q, J=7.2 Hz, 2H), 2.87(m, 2H), 2.71(s, 3H),2.47(m, 1H), 2.15(m, 2H), 1.92(m, 2H), 1.4-1.8(m, 6H), 1.36(t, J=7.2 Hz,3H), 1.24(m, 2H). 444 7H

δ(CDCl₃)δ6.71(m, 2H), 6.60(m, 1H), 4.38(m, 1H), 4.20(m, 1H), 3.87(m,2H), 3.68(m, 1H), 2.85(m, 4H), 2.70(s, 3H), 2.46(m, 1H), 2.14 (m, 2H),1.6-2.0(m, 8H), 1.55(m, 2H), 1.25(m, 2H), 1.05(t, J=7.2 Hz, 3H). 458 7I

δ(CDCl₃)δ6.72(m, 2H), 6.62(m, 1H), 4.41(m, 1H), 4.19(m, 1H), 3.92(m,2H), 3.71(m, 1H), 3.17(m, 1H), 2.96(m, 2H), 2.71(s, 3H), 2.47 (m, 1H),2.15(m, 2H), 1.92(m, 2H), 1.4-1.8(m, 6H), 1.33(d, J=7.6 Hz, 6H), 1.25(m,2H). 458 7J

δ(CDCl₃)δ6.72(m, 2H), 6.62(m, 1H), 4.39(m, 1H), 4.20(m, 1H), 3.88(m,2H), 3.71(m, 1H), 2.90(m, 2H), 2.71(s, 3H), 2.47(m, 1H), 2.26 (m, 1H),2.15(m, 2H), 1.92(m, 2H), 1.4-1.8(m, 6H), 1.25(m, 2H), 1.15 (m, 2H),0.98(m, 2H). 456

EXAMPLE 8A

[0314]

[0315] Step 1. Synthesis of 44

[0316] A mixture of 37 (6.42 g, 22.3 mmol), 3.5-dichlorophenyl boronicacid (12.8 g, 33.5 mmol), lithium chloride (4.02 g, 94.8 mmol), sodiumcarbonate (11.7 g, 110 mmol), and palladium tetrakis(triphenylphosphine)(2.01 g, 1.74 mmol) in DME (75 ml) and water (50 ml) was refluxed undernitrogen for 22 hours. The mixture was cooled to RT, diluted with CH₂Cl₂(200 ml), and washed with 1N NaOH (250 ml). The aqueous portion wasextracted with CH₂Cl₂ (2×150 ml) and the combined organic portion wasdried (K₂CO₃), concentrated, and purified by column chromatography(Hexanes gradient to EtOAc:Hexanes 1:20) to give 44 (3.60 g, 57%).¹H-NMR (CDCl₃) δ7.25 (m, 2H), 7.21 (m, 1H), 6.02 (m, 1H), 4.02 (s, 4H),2.60 (m, 2H), 2.46 (m, 2H), 1.90 (m, 2H).

[0317] Step 2. Synthesis of 45

[0318] A mixture of 44 (3.57 g, 12.5 mmol) and 10% Pt/C (0.357 g) inethanol (120 ml) was stirred under 1 atm hydrogen for 3 hours. Themixture was filtered, concentrated, and purified by columnchromatography (Hexanes gradient to EtOAc:Hexanes 1:100) to give 45(1.70 g, 47%). ¹H-NMR (CDCl₃) δ7.18 (m, 1H), 7.11 (m, 2H), 3.98 (s, 4H),2.51 (m, 1H), 1.6-1.9 (m, 8H).

[0319] Step 3. Synthesis of 46

[0320] A mixture of 45 (1.54 g, 5.36 mmol) and pyridiniump-toluenesulfonate (0.337 g, 1.34 mmol) in acetone (45 ml) and water (5ml) was refluxed for 24 hours. The mixture was concentrated and theresidue was partitioned between CH₂Cl₂ (150 ml) and water (100 ml). Theorganic portion was washed with 1N HCl (20 ml), 1N NaOH (20 ml), brine(50 ml), dried (K₂CO₃), and concentrated to give 46 (1.30 g, 95%).¹H-NMR (CDCl₃) δ7.24 (m, 1H), 7.12 (m, 2H), 2.99 (m, 1H), 2.51 (m, 4H),2.19 (m, 2H), 1.92 (m, 2H).

[0321] Step 4. Synthesis of 47

[0322] A solution of 46 (1.20 g, 4.93 mmol) and 1.0M L-selectride (5.5ml) in THF (15 ml) was stirred in dry ice-acetone bath for 2 hours andthen at RT for 16 hours. The reaction was quenched with drops of water,followed by 1N NaOH (10 ml) and aqueous H₂O₂ (10 ml). The mixture wasdiluted with saturated Na₂CO₃ (150 ml) and extracted by ether (3×50 ml).The combined organic portion was dried (Na₂SO₄), concentrated, andpurified by column chromatography (Hexanes gradient to EtOAc:Hexanes4.5:100) to give 47 (0.764 g, 63%). ¹H-NMR (CDCl₃) δ7.18 (m, 1H), 7.12(m, 2H), 4.13 (m, 1H), 2.50 (m, 1H), 1.86 (m, 4H), 1.65 (m, 4H).

[0323] Step 5. Synthesis of 48

[0324] To a solution 47 (0.764 g, 3.11 mmol) and triphenylphosphine(0.863 g, 3.29 mmol) in THF (10 ml) in an ice-water bath were addeddiethyl azodicarboxylate (0.649 g, 3.72 mmol) and diphenylphosphorylazide (0.978 g, 3.55 mmol). The mixture was allowed to warm to RT slowlyand stirred for 16 hours. The volatiles were removed under reducedpressure and the residue was purified by column chromatography (Hexanesgradient to EtOAc:Hexanes 0.75:100) to give 48 (0.626 g, 75%). ¹H-NMR(CDCl₃) δ7.20 (m, 1H), 7.07 (m, 2H), 3.33 (m, 1H), 2.48 (m, 1H), 2.14(m, 2H), 1.96 (m, 2H), 1.48 (m, 4H).

[0325] Step 6. Synthesis of 49

[0326] A mixture of 48 (0.626 g, 2.32 mmol) in EtOAc (10 ml) and water(0.2 ml) in an ice-water bath was treated with 1.0M trimethylphosphinein toluene (4.6 ml). The mixture was warmed to RT and stirred for 16hours. The mixture was evaporated to dryness and purified by columnchromatography (CH₂Cl₂ gradient to 7M NH₃/CH₃OH: CH₂Cl₂ 6:1000) to give49 (0.417 g, 74%). MS m/e 244 (M+H)⁺.

[0327] Step 7. Synthesis of 50

[0328] To a solution of 49 (0.417 g, 1.71 mmol) and pyridine (0.492 g,6.22 mmol) in THF (30 ml) in an ice-water bath was addedN,N′-disuccinimidyl carbonate (0.493 g, 1.93 mmol). The mixture wasstirred for 30 minutes and more pyridine (0.40 ml, 4.9 mmol) was added.The mixture was then stirred at RT for 3 hours. A solution of4-methylamino-1-Boc-piperidine (0.456 g, 2.13 mmol) in THF (10 ml) wasadded and the mixture was stirred at RT for 16 hours. The volatiles wereremoved under reduced pressure and the residue was partitioned betweenCH₂Cl₂ (65 ml) and 1N NaOH (50 ml). The organic portion was washedsequentially with 1N HCl (30 ml) and water (30 ml), dried (MgSO₄),concentrated, and purified by column chromatography (CH₂Cl₂ gradient toCH₃OH: CH₂Cl₂ 0.75:100) to give 50 (0.618 g, 75%). MS m/e 484 (M+H)⁺.

[0329] Step 8. Synthesis of 51

[0330] A solution of 50 (0.618 g, 1.28 mmol) in 4N HCl/dioxane (15 ml)was stirred at RT for 16 hours. The volatiles were removed under reducedpressure and the residue was partitioned between CH₂Cl₂ (2×40 ml) andconc. NH₄OH (40 ml). The organic portion was dried (MgSO₄) andconcentrated to give 51 (0.446 g, 91%). MS m/e 384 (M+H)⁺.

[0331] Step 9.

[0332] A solution of 51 (0.049 g, 0.13 mmol), acetic anhydride (0.015 g,0.15 mmol), and triethylamine (0.035 g, 0.35 mmol) in CH₂Cl₂ (5 ml) wasstirred at RT for 16 hours. The solution was diluted with CH₂Cl₂ (50 ml)and washed with 1N NaOH (25 ml) and 1N HCl (25 ml). The organic portionwas dried (MgSO₄), concentrated, and purified by PTLC (CH₃OH: CH₂Cl₂1:20) to give 8A (0.049 g, 89%).

EXAMPLE 8B

[0333]

[0334] A solution of 51 (0.035 g, 0.090 mmol), propionyl chloride (0.010g, 0.11 mmol), and triethylamine (0.020 g, 0.20 mmol) in CH₂Cl₂ (2.5 ml)was stirred at RT for 16 hours. The mixture was purified by PTLC (CH₃OH:CH₂Cl₂ 7:100) to give 8B (0.034 g, 86%).

[0335] Using essentially the same procedure, 8C, 8D, and 8E wereprepared.

EXAMPLE 8F

[0336]

[0337] A solution of 51 (0.048 g, 0.13 mmol), methanesulfonyl chloride(0.015 g, 0.13 mmol), and triethylamine (0.033 g, 0.33 mmol) in CH₂Cl₂(5 ml) was stirred at RT for 64 hours. The solution was diluted withCH₂Cl₂ (40 ml) and washed with 1N NaOH (20 ml). The organic portion wasdried (MgSO₄), concentrated, and purified by PTLC (CH₃OH: CH₂Cl₂ 1:20)to give 8F (0.053 g, 91%).

[0338] Using essentially the same procedure, 8G, 8H, and 8I wereprepared. Example ¹H NMR MS(M + H)⁺ 8A

CDCl₃(CDCl₃)δ7.18(m, 1H), 7.07(m, 2H), 4.73(m, 1H), 4.46(m, 1H), 4.21(m,1H), 3.86(m, 1H), 3.69 (m, 1H), 3.14(m, 1H), 2.68(s, 3H), 2.58(m, 1H),2.44(m, 1H), 2.14 (m, 2H), 2.10(s, 3H), 1.90(m, 2H), 1.4-1.8(m, 6H),1.26(m, 2H). 426 8B

CDCl₃(CDCl₃)δ7.18(m, 1H), 7.08(m, 2H), 4.75(m, 1H), 4.46(m, 1H), 4.19(m,1H), 3.92(m, 1H), 3.71 (m, 1H), 3.10(m, 1H), 2.68(s, 3H), 2.59(m, 1H),2.44(m, 1H), 2.35(q, J=7.6 Hz, 2H), 2.15(m, 2H), 1.91 (m, 2H),1.4-1.8(m, 6H), 1.26(m, 2H), 1.15(t, J=7.6 Hz, 3H). 440 8C

CDCl₃(CDCl₃)δ7.18(m, 1H), 7.08(m, 2H), 4.76(m, 1H), 4.46(m, 1H), 4.18(m,1H), 3.93(m, 1H), 3.72 (m, 1H), 3.10(m, 1H), 2.68(s, 3H), 2.57(m, 1H),2.44(m, 1H), 2.29 (m, 2H), 2.16(m, 2H), 1.90(m, 2H), 1.4-1.8(m, 8H),1.26(m, 2H), 0.97 (t, J=7.4 Hz, 3H). 454 8D

CDCl₃(CDCl₃)δ7.18(m, 1H), 7.07(m, 2H), 4.75(m, 1H), 4.46(m, 1H), 4.19(m,1H), 3.99(m, 1H), 3.72 (m, 1H), 3.11(m, 1H), 2.80(m, 1H), 2.68(s, 3H),2.57(m, 1H), 2.44(m, 1H), 2.17(m, 2H), 1.91(m, 2H), 1.4-1.8(m, 6H),1.26(m, 2H), 1.12 (m, 6H). 454 8E

CDCl₃(CDCl₃)δ7.18(m, 1H), 7.07(m, 2H), 4.71(m, 1H), 4.48(m, 1H), 4.30(m,1H), 4.21(m, 1H), 3.71 (m, 1H), 3.15(m, 1H), 2.69(s, 3H), 2.63(m, 1H),2.45(m, 1H), 2.16 (m, 2H), 1.92(m, 2H), 1.4-1.8(m, 7H), 1.26(m, 2H),0.98(m, 2H), 0.75(m, 2H). 452 8F

CDCl₃(CDCl₃)δ7.18(m, 1H), 7.07(m, 2H), 4.39(m, 1H), 4.23(m, 1H), 3.88(m,2H), 3.69(m, 1H), 2.79(s, 3H), 2.76(m, 2H), 2.72(s, 3H), 2.45(m, 1H),2.15(m, 2H), 1.92 (m, 2H), 1.75(m, 4H), 1.56(m, 2H), 1.25(m, 2H). 462 8G

CDCl₃(CDCl₃)δ7.18(m, 1H), 7.07(m, 2H), 4.39(m, 1H), 4.22(m, 1H), 3.90(m,2H), 3.69(m, 1H), 2.95(q, J=7.4 Hz, 2H), 2.87(m, 2H), 2.71 (s, 3H),2.45(m, 1H), 2.15(m, 2H), 1.91(m, 2H), 1.72(m, 4H), 1.56 (m, 2H),1.36(t, J=7.4 Hz, 3H), 1.25(m, 2H). 476 8H

CDCl₃(CDCl₃)δ7.18(m, 1H), 7.07(m, 2H), 4.39(m, 1H), 4.21(m, 1H), 3.89(m,2H), 3.69(m, 1H), 2.86 (m, 4H), 2.71(s, 3H), 2.44(m, 1H), 2.15(m, 2H),1.87(m, 4H), 1.71 (m, 4H), 1.55(m, 2H), 1.25(m, 2H), 1.06(t, J=7.6 Hz,3H). 490 8I

CDCl₃(CDCl₃)δ7.18(m, 1H), 7.08(m, 2H), 4.41(m, 1H), 4.21(m, 1H), 3.92(m,2H), 3.70(m, 1H), 3.18 (m, 1H), 2.96(m, 2H), 2.71(s, 3H), 2.45(m, 1H),2.15(m, 2H), 1.91 (m, 2H), 1.68(m, 4H), 1.56(m, 2H), 1.33(d, J=6.4 Hz,6H), 1.27(m, 2H). 490

EXAMPLE 9A

[0339]

[0340] Step 1. Synthesis of 52

[0341] To a solution of 1M ZnEt₂ in hexanes (7.3 ml) in CH₂Cl₂ (8 ml) inan ice-water bath was added TFA (0.842 g, 7.38 mmol) in CH₂Cl₂ (6 ml)dropwise. Upon stirring for 20 minutes, a solution of CH₂l₂ (2.08 g,7.78 mmol) in CH₂Cl₂ (4 ml) was added. After an additional 20 minutes,44 (1.01 g, 3.53 mmol) in CH₂Cl₂ (5 ml) was added and the reaction wasstirred at RT for 40 hours. The mixture was cooled in an ice-water bathand quenched with CH₃OH (5 ml), washed with 1N NaOH (60 ml), dried(MgSO₄), and purified by column chromatography (Hexanes gradient toEtOAc:Hexanes 1:200) to give 52 (0.608 g, 57%). ¹H-NMR (CDCl₃) δ7.17 (m,2H), 7.15 (m, 1H), 3.90 (m, 4H), 2.19 (m, 3H), 1.80 (m, 1H), 1.63 (m,1H), 1.46 (m, 1H), 1.24 (m, 1H), 1.01 (m, 1H), 0.78 (m, 1H).

[0342] Step 2. Synthesis of 53

[0343] A mixture of 52 (0.606 g, 2.03 mmol) and water (1 ml) in 1:1TFA-CH₂Cl₂ (10 ml) was stirred at RT for 2 hours. The volatiles wereremoved under reduced pressure and the residue was partitioned betweenEtOAc (50 ml) and saturated Na₂CO₃ (40 ml). The organic portion wasdried (MgSO₄) and purified by column chromatography (Hexanes gradient toEtOAc:Hexanes 1:50) to give 53 (0.460 g, 89%). ¹H-NMR (CDCl₃) δ7.20 (m,1H), 7.17 (m, 2H), 2.84 (m, 1H), 2.68 (m, 1H), 2.42 (m, 2H), 2.26 (m,2H), 1.49 (m, 1H), 1.07 (m, 1H), 0.88 (m, 1H).

[0344] Step 3. Synthesis of 54 and 55

[0345] A solution of 53 (0.460 g, 1.80 mmol) and 1M L-selectride (2.0ml) in THF (7.5 ml) was stirred in a dry ice-acetone bath for 2 hoursand then at RT for 3 hours. More 1M L-selectride (0.6 ml) was added andthe solution was stirred at RT for 16 hours. The reaction was quenchedwith several drops of water, 1N NaOH (5 ml), and aqueous H₂O₂ (5 ml).The mixture was diluted with saturated Na₂CO₃ (80 ml) and extracted withether (2×50 ml). The combined organic portion was dried (MgSO₄) andpurified by PTLC (CH₃OH: CH₂Cl₂ 1:100) to give 54 (0.210 g, 45%) and 55(0.216 g, 47%).

[0346] 54 ¹H-NMR (CDCl₃) δ7.15 (m, 1H), 7.09 (m, 2H), 3.69 (m, 1H), 2.47(m, 1H), 2.22 (m, 1H), 1.98 (m, 1H), 1.74 (m, 1H), 1.68 (m, 1H), 1.48(m, 1H), 1.22 (m, 2H), 0.98 (m, 1H), 0.78 (m, 1H).

[0347] 55 ¹H-NMR (CDCl₃) δ7.17 (m, 3H), 3.81 (m, 1H), 2.23 (m, 1H), 1.98(m, 3H), 1.60 (m, 1H), 1.49 (m, 2H), 1.22 (m, 1H), 1.00 (m, 1H), 0.58(m, 1H).

[0348] Step 4. Synthesis of 56

[0349] To a solution of 54 (0.209 g, 0.813 mmol) and triphenylphosphine(0.226 g, 0.862 mmol) in THF (5 ml) in an ice-water bath were addeddiethyl azodicarboxylate (0.222 g, 1.27 mmol) and diphenylphosphorylazide (0.293 g, 1.06 mmol). The ice-water bath was removed and themixture was stirred at RT for 16 hours. The volatiles were removed underreduced pressure and the residue was purified by PTLC (EtOAc:Hexanes1:20) to give 56 (0.113 g, 49%). ¹H-NMR (CDCl₃) δ7.17 (m, 3H), 3.56 (m,1H), 2.16 (m, 2H), 1.98 (m, 2H), 1.67 (m, 1H), 1.50 (m, 1H), 1.24 (m,1H), 1.03 (m, 1H), 0.59(m, 1H).

[0350] Step 5. Synthesis of 57

[0351] A mixture of 56 (0.112 g, 0.397 mmol) and 1M trimethylphosphinein toluene (0.8 ml) in EtOAc (5 ml) and water (50 μl) was stirred at RTfor 16 hours. The mixture was evaporated to dryness and purified by PTLC(7M NH₃/CH₃OH:CH₂Cl₂ 1:50 ) to give 57 (0.093 g, 92%). MS m/e 256(M+H)⁺.

[0352] Step 6. Synthesis of 58

[0353] To a mixture of 57 (0.093 g, 0.364 mmol) and N,N′-disuccinimidylcarbonate (0.120 g, 0.469 mmol) in THF (5 ml) in an ice-water bath wasadded pyridine (0.190 g, 2.40 mmol). The mixture was stirred at 0° C.for 30 minutes then at RT for 3 hours. A solution of4-methylamino-1-Boc-piperidine (0.098 g, 0.458 mmol) in THF (5 ml) wasadded and the mixture was stirred at RT for 16 hours. The volatiles wereremoved under reduced pressure and the residue was partitioned betweenCH₂Cl₂ (40 ml) and 1N NaOH (30 ml). The organic portion was dried(MgSO₄) and purified by PTLC (CH₃OH:CH₂Cl₂ 1:33) to give 58 (0.169 g,94%). MS m/e 496 (M+H)⁺.

[0354] Step 7. Synthesis of 59

[0355] A solution of 58 (0.169 g, 0.341 mmol) in 1:1 TFA-CH₂Cl₂ (10 ml)in an ice-water bath was stirred for 30 minutes and then stirred at RTfor 16 hours. The volatiles were removed under reduced pressure and theresidue was partitioned between CH₂Cl₂ (50 ml) and conc. NH₄OH (25 ml).The organic portion was dried (MgSO₄) and evaporated to give 59 (0.114g, 84%). MS m/e 396 (M+H)⁺.

[0356] Step 8.

[0357] A solution of 59 (0.027 g, 0.069 mmol), acetic anhydride (0.0088g, 0.086 mmol), and triethylamine (0.013 g, 0.13 mmol) in CH₂Cl₂ (5 ml)was stirred at RT for 16 hours. The mixture was evaporated to drynessand purified by PTLC (CH₃OH:CH₂Cl₂ 1:20) to give 9A (0.029 g, 97%).

EXAMPLE 9B

[0358]

[0359] A solution of 59 (0.033 g, 0.082 mmol), methanesulfonyl chloride(0.011 g, 0.096 mmol), and triethylamine (0.020 g, 0.20 mmol) in CH₂Cl₂(5 ml) was stirred at RT for 16 hours. The mixture was evaporated todryness and purified by PTLC (CH₃OH:CH₂Cl₂ 1:20) to give 9B (0.037 g,95%). Example ¹H NMR MS (M + H)⁺ 9A

(CDCl₃) δ 7.15(m, 1H), 7.11(m, 2H), 4.73(m, 1H), 4.43(m, 1H), 4.28(m,1H), 3.87(m, 1H), 3.70(m, 1H), 3.13(m, 1H), 2.69(s, 3H), 2.57(m, 1H),2.10(m, 6H), 1.2-1.9(m, 8H), 1.04(m, 1H), 0.71(m, 1H). 438 9B

(CDCl₃) δ 7.15(m, 1H), 7.10(m, 2H), 4.34(m, 2H), 3.88(m, 2H), 3.69(m,1H), 2.78(s, 3H), 2.75(m, 2H), 2.72(s, 3H), 2.09(m, 3H), 1.74(m, 5H),1.43(m, 2H), 1.29(m, 1H), 1.03(m, 1H), 0.71(m, 1H). 474

EXAMPLE 10A

[0360]

[0361] Step 1. Synthesis of 60

[0362] To a solution of 55 (0.216 g, 0.842 mmol) and triphenylphosphine(0.246 g, 0.938 mmol) in THF (5 ml) in an ice-water bath were addeddiethyl azodicarboxylate (0.200 g, 1.15 mmol) and diphenylphosphorylazide (0.268 g, 0.974 mmol). The ice-water bath was removed and themixture was stirred at RT for 16 hours. The volatiles were removed underreduced pressure and the residue was purified by PTLC (EtOAc:Hexanes1:20) to give 60 (0.142 g, 60%). ¹H-NMR (CDCl₃) δ7.17 (m, 1H), 7.10 (m,2H), 3.37 (m, 1H), 2.47 (m, 1H), 2.27 (m, 1H), 1.97 (m, 1H), 1.83 (m,1H), 1.58 (m, 1H), 1.28 (m, 2H), 1.03 (m, 1H), 0.77 (m, 1H).

[0363] Step 2. Synthesis of 61

[0364] A mixture of the 60 (0.142 g, 0.504 mmol) and 1Mtrimethylphosphine in toluene (1.0 ml) in EtOAc (5 ml) and water (100μl) was stirred at RT for 16 hours. The mixture was evaporated todryness and purified by PTLC (7M NH₃/CH₃OH:CH₂Cl₂ 1:33) to give 61(0.102 g, 79%). MS m/e 256 (M+H)⁺.

[0365] Step 3. Synthesis of 62

[0366] To a mixture of 61 (0.102 g, 0.398 mmol) and N,N′-disuccinimidylcarbonate (0.134 g, 0.524 mmol) in THF (5 ml) in an ice-water bath wasadded pyridine (0.280 g, 3.54 mmol). The mixture was stirred at 0° C.for 30 minutes then at RT for 3 hours. A solution of4-methylamino-1-Boc-piperidine (0.120 g, 0.561 mmol) in THF (4 ml) wasadded and the mixture was stirred at RT for 16 hours. The volatiles wereremoved under reduced pressure and the residue was partitioned betweenCH₂Cl₂ (50 ml) and 0.5N HCl (30 ml). The organic portion was washed with1N NaOH (30 ml), dried (MgSO₄), and concentrated. The resulting solidwas taken up in 4N HCl/dioxane (5 ml) and stirred at RT for 16 hours.The volatiles were removed under reduced pressure and the residue waspartitioned between EtOAc (2×40 ml) and conc. NH₄OH (35 ml). The organicportion was dried (K₂CO₃), concentrated, and purified by PTLC (2.3MNH₃/CH₃OH:CH₂Cl₂ 3:17) to give 62 (0.089 g, 56%). ¹H-NMR (CD₃OD) δ7.21(m, 3H), 4.15 (m, 1H), 3.60 (m, 1H), 3.11 (m, 2H), 2.73 (s, 3H), 2.67(m, 2H), 2.44 (m, 1H), 2.23 (m, 1H), 2.04 (m, 1H), 1.64 (m, 5H), 1.45(m, 1H), 1.26 (m, 2H), 0.97 (m,1H), 0.79 (m,1H).

[0367] Step 4.

[0368] A solution of the 62 (0.022 g, 0.055 mmol), acetic anhydride(0.0069 g, 0.067 mmol), and triethylamine (0.012 g, 0.12 mmol) in CH₂Cl₂(5 ml) was stirred at RT for 16 hours. The mixture was evaporated todryness and purified by PTLC (CH₃OH:CH₂Cl₂ 1:20) to give 10A (0.024 g,98%).

[0369] Using essentially the same procedure, 10B was prepared.

EXAMPLE 10C

[0370]

[0371] A solution of 62 (0.026 g, 0.068 mmol), isobutyryl chloride(0.0075 g, 0.070 mmol), and triethylamine (0.012 g, 0.12 mmol) in CH₂Cl₂(3 ml) was stirred at RT for 16 hours. The mixture was evaporated todryness and purified by PTLC (CH₃OH:CH₂Cl₂ 1:20) to give 10C (0.029 g,90%).

EXAMPLE 10D

[0372]

[0373] A solution of 62 (0.022 g, 0.056 mmol), methanesulfonyl chloride(0.0087 g, 0.075 mmol), and triethylamine (0.011 g, 0.11 mmol) in CH₂Cl₂(5 ml) was stirred at RT for 16 hours. The mixture was evaporated todryness and purified by PTLC (CH₃OH:CH₂Cl₂ 1:20) to give 10D (0.027 g,100%). Example ¹H NMR MS (M + H)⁺ 10A

(CDCl₃) δ 7.15(m, 1H), 7.12(m, 2H), 4.72(m, 1H), 4.44(m, 1H), 4.08(m,1H), 3.86(m, 1H), 3.65(m, 1H), 3.14(m, 1H), 2.66(s, 3H), 2.57(m, 2H),2.21(m, 1H), 2.10(s, 3H), 2.05(m, 1H), 1.83(m, 1H), 1.68(m, 2H), 1.51(m,2H), 1.27(m, 2H), 1.08(m, 1H), 0.98(m, 1H), 0.70(m, 1H). 438 10B

(CDCl₃) δ 7.15(m, 1H), 7.11(m, 2H), 4.75(m, 1H), 4.43(m, 1H), 4.08(m,1H), 3.90(m, 1H), 3.66(m, 1H), 3.09(m, 1H), 2.66(s, 3H), 2.57(m, 2H),2.35(q, J=7.2Hz, 2H), 2.21(m, 1H), 2.05(m, 1H), 1.83(m, 1H), 1.68(m,2H), 1.47(m, 2H), 1.28(m, 2H), 1.14(t, J=7.2Hz, 3H), 1.06(m, 1H),0.98(m, 1H), 0.70(m, 1H). 452 10C

(CDCl₃) δ 7.15(m, 1H), 7.12(m, 2H), 4.76(m, 1H), 4.45(m, 1H), 4.07(m,1H), 3.99(m, 1H), 3.65(m, 1H), 3.10(m, 1H), 2.80(m, 1H), 2.66(s, 3H),2.57(m, 2H), 2.21(m, 1H), 2.06(m, 1H), 1.4-1.9(m, 5H), 1.29(m, 2H),1.12(m, 7H), 0.98(m, 1H), 0.71(m, 1H). 466 10D

(CDCl₃) δ 7.15(m, 1H), 7.12(m, H), 4.38(m, 1H), 4.10(m, 1H), 3.88(m,2H), 3.66(m, 1H), 2.79(s, 3H), 2.75(m, 2H), 2.70(s, 3H), 2.57(m, 1H),2.23(m, 1H), 2.06(m, 1H), 1.76(m, 5H), 1.29(m, 2H), 1.09(m, 1H), 0.99(m,1H), 0.71(m, 1H). 474

EXAMPLE 11A

[0374]

[0375] Step 1. Synthesis of 63

[0376] A solution of 44 (2.85 g, 10.0 mmol) and pyridiniump-toluenesulfonate (0.628 g, 2.50 mmol) in acetone (90 ml) and water (10ml) was refluxed for 20 hours. The mixture was concentrated and theresidue was partitioned between CH₂Cl₂ (200 ml) and water (100 ml). Theorganic portion was washed with 1N HCl (30 ml), 1N NaOH (30 ml), brine(50 ml), dried (K₂CO₃), concentrated, and purified by columnchromatography (Hexanes gradient to EtOAc:Hexanes 3:100) to give 63(1.82 g, 76%). ¹H-NMR (CDCl₃) δ7.27 (m, 3H), 6.15 (m, 1H), 3.08 (m, 2H),2.84 (m, 2H), 2.64 (m, 2H).

[0377] Step 2. Synthesis of 64

[0378] A mixture of 63 (1.20 g, 4.98 mmol) and sodium borohydride (0.230g, 6.08 mmol) in MeOH (50 ml) was stirred at 0° C. for 2 hours. Water(2.5 ml) was added and the mixture was stirred for 30 minutes. Themixture was then concentrated and the residue was partitioned betweenCH₂Cl₂ (150 ml) and water (100 ml). The organic portion was dried(K₂CO₃) and concentrated to give 64 (1.15 g, 95%). ¹H-NMR (CDCl₃) δ7.23(m, 2H), 7.20 (m, 1H), 6.03 (m, 1H), 4.05 (m, 1H), 2.54 (m, 2H), 2.44(m, 1H), 2.20 (m, 1H), 1.98 (m, 1H), 1.83 (m, 1H).

[0379] Step 3. Synthesis of 65

[0380] To a solution of 64 (1.00 g, 4.12 mmol) and triphenylphosphine(1.13 g, 4.30 mmol) in THF (12 ml) in an ice-water bath were addeddiethyl azodicarboxylate (0.857 g, 4.92 mmol) and diphenylphosphorylazide (1.30 g, 4.72 mmol). The ice-water bath was removed and themixture was stirred at RT for 16 hours. The volatiles were removed underreduced pressure and the residue was taken up in CH₂Cl₂ (100 ml), washedwith water and saturated sodium bicarbonate, dried (K₂CO₃), and purifiedby column chromatography (Hexanes) to give 65 (0.272 g, 25%). ¹H-NMR(CDCl₃) δ7.23 (m, 3H), 6.04 (m, 1H), 3.76 (m, 1H), 2.54 (m, 2H), 2.45(m, 1H), 2.30 (m, 1H), 2.07 (m, 1H), 1.88 (m, 1H).

[0381] Step 4. Synthesis of 66

[0382] A mixture of the 65 (0.300 g, 1.12 mmol) and 1Mtrimethylphosphine in toluene (2.24 ml) in EtOAc (5 ml) and water (100μl) was stirred at RT for 16 hours. The mixture was evaporated todryness and purified by column chromatography (2M NH₃/CH₃OH:CH₂Cl₂ 1:20)to give 66 (0.266 g, 98%). MS m/e 242 (M+H)⁺.

[0383] Step 5. Synthesis of 67

[0384] To a mixture of 66 (0.266 g, 1.10 mmol) and N,N′-disuccinimidylcarbonate (0.338 g, 1.32 mmol) in THF (20 ml) in an ice-water bath wasadded pyridine (0.70 ml, 8.6 mmol). The mixture was stirred at 0° C. for30 minutes then at RT for 2 hours. A solution of4-methylamino-1-Boc-piperidine (0.259 g, 1.21 mmol) in THF (5 ml) wasadded and the mixture was stirred at RT for 16 hours. The volatiles wereremoved under reduced pressure and the residue was partitioned betweenCH₂Cl₂ (100 ml) and 1N NaOH (50 ml). The organic portion was washed withwater and brine, dried (K₂CO₃), concentrated, and purified by columnchromatography (CH₂Cl₂ gradient to MeOH:CH₂Cl₂ 1:50) to give 67 (0.520g, 98%). ¹H-NMR (CDCl₃) δ7.24 (m, 2H), 7.22 (m, 1H), 6.09 (m, 1H), 4.34(m, 2H), 4.18 (m, 2H), 4.05 (m, 1H), 2.78 (m, 2H), 2.69 (s, 3H), 2.63(m, 1H), 2.48 (m, 2H), 2.06 (m, 2H), 1.72 (m, 1H), 1.61 (m, 2H), 1.51(m, 2H), 1.46 (s, 9H).

[0385] Step 6. Synthesis of 68

[0386] A solution of 67 (0.420 g, 0.871 mmol) in 4N HCl/dioxane (10 ml)and CH₂Cl₂ (10 ml) stirred at RT for 2 hours. The mixture wasconcentrated to give 68 (0.360 g, 99%). ¹H-NMR (CD₃OD) δ7.34 (m, 2H),7.27 (m, 1H), 6.16 (m, 1H), 4.34 (m, 1H), 3.89 (m, 1H), 3.48 (m, 2H),3.10 (m, 2H), 2.81 (s, 3H), 2.52 (m, 3H), 1.6-2.3 (m, 7H).

[0387] Step 7.

[0388] A solution of the 68 (0.050 g, 0.12 mmol), acetic anhydride (40μl, 0.42 mmol), and triethylamine (200 μl, 1.42 mmol) in CH₂Cl₂ (5 ml)was stirred at RT for 4 hours. The mixture was evaporated to dryness andpurified by PTLC (CH₃OH:CH₂Cl₂ 1:10) to give 11A (0.038 g, 75%).

[0389] Using essentially the same procedure, 11B was prepared. Example¹H NMR MS (M + H)⁺ 11A

(CDCl₃) δ 7.24(m, 2H), 7.22(m, 1H), 6.09(m, 1H), 4.73(m, 1H), 4.47(m,1H), 4.32(m, 1H), 4.04(m, 1H), 3.86(m, 1H), 3.14(m, 1H), 2.68(s, 3H),2.4-2.65(m, 4H), 2.10(s, 3H), 2.06(m, 2H), 1.69(m, 3H), 1.52(m, 2H). 42411B

(CDCl₃) δ 7.23(m, 2H), 7.20(m, 1H), 6.07(m, 1H), 4,74(m, 1H), 4.46(m,1H), 4.34(m, 1H), 4.04(m, 1H), 3.90(m, 1H), 3.08(m, 1H), 2.67(s, 3H),2.4-2.65(m, 4H), 2.34(q, J=7.2Hz, 2H), 2.06(m, 2H), 1.69(m, 3H), 1.49(m,2H), 1.13(t, J=7.2Hz, 3H). 438

EXAMPLE 12A

[0390]

[0391] Step 1. Synthesis of 69

[0392] To a suspension of methoxymethylenetriphenylphosphonium chloride(16.4 g, 47.8 mmol) in THF (30 ml) in an ice-water bath was addedpotassium t-butoxide (6.72 g, 60.0 mmol) in t-butanol (40 ml). Themixture was stirred at 0° C. for 1 hour. 3′-Fluoroacetophenone (5.00 g,36.2 mmol) was added and the mixture was stirred at RT for 3 hours. Thereaction was diluted with water (100 ml) and extracted wit ether (2×100ml). The organic portion was washed with brine, dried (MgSO₄),concentrated, and purified by column chromatography (Hexanes) to give 69(4.80 g, 80%). ¹H-NMR (CDCl₃) δ7.2-7.5 (m, 2H), 7.08 (m, 0.5H), 6.99 (m,0.5H), 6.86 (m, 1H), 6.46 (m, 0.5H), 6.16 (m, 0.5H), 3.74 (s, 1.5H),3.71 (s, 1.5H), 1.97 (m, 1.5H), 1.91 (m,1.5H).

[0393] Step 2. Synthesis of 70

[0394] A solution of 69 (4.80 g, 28.9 mmol) and p-toluenesulfonic acid(0.338 g, 1.78 mmol) in dioxane (90 ml) and water (18 ml) was refluxedfor 20 hours. The mixture was diluted with water (100 ml) and extractedwith ether (2×200 ml). The combined organic portion was washed withbrine, dried (MgSO₄), and purified by column chromatography (Hexanesgradient to EtOAc:Hexanes 1:100) to give 70 (1.90 g, 43%). ¹H-NMR(CDCl₃) δ9.68 (d, J=1.6 Hz, 1H), 7.35 (m,1H), 7.01 (m, 2H), 6.93 (m,1H), 3.64 (m, 1H), 1.45 (d, J=7.6 Hz, 3H).

[0395] Step 3. Synthesis of 71

[0396] To a solution of 70 (1.90 g, 12.5 mmol) in EtOH (120 ml) andether (60 ml) in an ice-water bath were added potassium hydroxide (0.21g, 3.7 mmol) and methyl vinyl ketone (1.31 g, 18.7 mmol). The mixturewas then warmed to RT and stirred for 16 hours. The mixture wasneutralized with 5% citric acid, concentrated, and partitioned betweenCH₂Cl₂ (2×150 ml) and aqueous sodium bicarbonate. The combined organicportion was washed with brine, dried (MgSO₄), and purified by columnchromatography (Hexanes gradient to EtOAc:Hexanes 1:20) to give 71 (2.00g, 78%). MS m/e 205 (M+H)⁺.

[0397] Step 4. Synthesis of 72 and 73

[0398] A mixture of 71 (1.02 g, 5.00 mmol), aminodiphenylmethane (1.10g, 6.00 mmol), and sodium triacetoxyborohydride (2.56 g, 12.1 mmol) indichloroethane (150 ml) was stirred at RT for 48 hours. The mixture wasdiluted with CH₂Cl₂ (150 ml) and washed with conc. NH₄OH (100 ml). Theorganic portion was washed with brine, dried (K₂CO₃), and purified bycolumn chromatography (Hexanes gradient to EtOAc:Hexanes 1:200) to give72 (0.960 g, 52%) and 73 (0.320 g, 18%).

[0399] 72 ¹H-NMR (CDCl₃) δ7.42 (m, 3H), 7.0-7.35 (m, 10H), 6.86 (m, 1H),5.97 (m, 1H), 5.70 (m, 1H), 5.06 (s, 1H), 3.11 (m, 1H), 1.90 (m, 2H),1.57 (m, 2H), 1.31 (s, 3H), 1.21 (m, 1H).

[0400] 73 ¹H-NMR (CDCl₃) δ7.42 (m, 3H), 7.15-7.35 (m, 8H), 7.05 (m, 2H),6.85 (m, 1H), 5.97 (m, 1H), 5.70 (m, 1H), 5.06 (s, 1H), 3.09 (m, 1H),1.4-2.0 (m, 4H), 1.38 (s, 3H), 1.21 (m, 1H).

[0401] Step 5. Synthesis of 74

[0402] A mixture of 72 (0.660 g, 1.78 mmol), ammonium formate (1.90 g,30.2 mmol), and 10% Pd/C (0.120 g) in CH₃OH (50 ml) was stirred at RTfor 2 days. The mixture was filtered and concentrated. The residue wastaken up in CH₂Cl₂ (150 ml) and washed with conc. NH₄OH (20 ml),saturated sodium bicarbonate, and brine. The organic portion was dried(K₂CO₃), concentrated, and purified by column chromatography (CH₂Cl₂gradient to 2M NH₃/CH₃OH: CH₂Cl₂ 1:20) to give 74 (0.400 g, 100%). MSm/e 208 (M+H)⁺.

[0403] Step 6.

[0404] To an ice-cooled solution of 74 (0.041 g, 0.20 mmol) and pyridine(200 μl, 2.45 mmol) in THF (5 ml) was added N,N′-disuccinimidylcarbonate (0.072 g, 0.28 mmol). The mixture was stirred at RT for 6hours. N-Methyl-1-(methylsulfonyl)-4-piperidineamine (0.042 g, 0.22mmol) was added at 0° C. and the mixture was stirred at RT for 16 hours.The mixture was diluted with CH₂Cl₂ (50 ml) and washed with 1N NaOH (20ml), 1N HCl (20 ml), saturated sodium bicarbonate, and brinesequentially. The organic portion was dried (MgSO₄), concentrated, andpurified by PTLC (CH₃OH: CH₂Cl₂ 1:20) to give 12A (0.045 g, 53%).

[0405] Using essentially the same procedure, 12B and 12C were preparedfrom 74.

[0406] Using essentially the same procedure, 12D, 12E, and 12F wereprepared from 73. MS Example ¹H NMR (M + H)⁺ 12A

(CDCl₃) δ 7.30(m, 1H), 7.14(m, 1H), 7.05(m, 1H), 6.89(m, 1H), 4.34(m,1H), 4.02(m, 1H), 3.86(m, 2H), 3.74(m, 1H), 2.77(s, 3H), 2.72(m, 2H),2.61(s, 3H), 2.29(m, 2H), 1.85(m, 2H), 1.5-1.8(m, 6H), 1.14(s, 3H),1.10(m, 2H). 426 12B

(CDCl₃) δ 7.30(m, 1H), 7.14(m, 1H), 7.05(m, 1H), 6.89(m, 1H), 4.33(m,1H), 4.03(m, 1H), 3.87(m, 2H), 3.74(m, 1H), 2.94(q, J=7.4Hz, 2H),2.84(m, 2H), 2.60(s, 3H), 2.28(m, 2H), 1.85(m, 2H), 1.5-1.8(m, 6H),1.34(t, J=7.4Hz, 3H), 1.14(s, 3H), 1.10(m, 2H). 440 12C

(CDCl₃) δ 7.30(m, 1H), 7.14(m, 1H), 7.05(m, 1H), 6.89(m, 1H), 4.70(m,1H), 4.40(m, 1H), 4.01(m, 1H), 3.83(m, 1H), 3.74(m, 1H), 3.11(m, 1H),2.57(s, 3H), 2.54(m, 1H), 2.28(m, 2H), 2.08(s, 3H), 1.87(m, 2H),1.4-1.8(m, 6H), 1.14(s, 3H), 1.10(m, 2H). 390 12D

(CDCl₃) δ 7.27(m, 1H), 7.15(m, 1H), 7.06(m, 1H), 6.88(m, 1H), 4.40(m,1H), 4.31(m, 1H), 3.88(m, 2H), 3.68(m, 1H), 2.79(s, 3H), 2.76(m, 2H),2.74(s, 3H), 1.4-2.0(m, 11H), 1.26(s, 3H), 1.20(m, 1H). 426 12E

(CDCl₃) δ 7.27(m, 1H), 7.15(m, 1H), 7.06(m, 1H), 6.88(m, 1H), 4.40(m,1H), 4.29(m, 1H), 3.91(m, 2H), 3.66(m, 1H), 2.96(q, J=7.4Hz, 2H),2.86(m, 2H), 2.73(s, 3H), 1.92(m, 2H), 1.81(m, 4H), 1.71(m, 4H), 1.49(m,2H), 1.36(t, J=7.4Hz, 3H), 1.26(s, 3H). 440 12F

(CDCl₃) δ 7.27(m, 1H), 7.15(m, 1H), 7.06(m, 1H), 6.88(m, 1H), 4.73(m,1H), 4.47(m, 1H), 4.28(m, 1H), 3.86(m, 1H), 3.68(m, 1H), 3.14(m, 1H),2.71(s, 3H), 2.57(m, 1H), 2.10(s, 3H), 1.93(m, 2H), 1.81(m, 3H), 1.68(m,3H), 1.51(m, 4H), 1.26(s, 3H). 390

EXAMPLE 13A

[0407]

[0408] Step 1. Synthesis of 75

[0409] To an ice-cooled suspension ofmethoxymethylenetriphenylphosphonium chloride (13.2 g, 38.4 mmol) in THF(30 ml) was added potassium t-butoxide (5.38 g, 48.0 mmol) in t-butanol(40 ml). The mixture was stirred at 0° C. for 1.5 hours.3′,5′-Difluoroacetophenone (5.00 g, 32.0 mmol) was added and the mixturewas stirred at RT for 16 hours. The reaction was diluted with water (100ml) and extracted with ether (2×200 ml). The organic portion was washedwith brine, dried (Na₂SO₄), concentrated, and purified by columnchromatography (Hexanes) to give 75 (4.80 g, 68%). ¹H-NMR (CDCl₃) δ7.17(m, 1H), 6.79 (m, 1H), 6.61 (m, 1H), 6.49 (m, 0.5H), 6.20 (m, 0.5H),3.75 (s, 1.5H). 3.73 (s, 1.5H), 1.93 (m, 1.5H), 1.88 (m, 1.5H).

[0410] Step 2. Synthesis of 76

[0411] A solution of 75 (4.80 g, 26.1 mmol) and p-toluenesulfonic acid(0.338 g,1.78 mmol) in dioxane (90 ml) and water (18 ml) was refluxedfor 20 hours. The mixture was diluted with water (100 ml) and extractedwith ether (2×200 ml). The combined organic portion was washed withbrine, dried (Na₂SO₄), filtered and purified by column chromatography(Hexanes gradient to EtOAc:Hexanes 1:100) to give 76 (1.80 g, 41%).¹H-NMR (CDCl₃) δ9.66 (d, J=1.2 Hz, 1H), 6.74 (m, 3H), 3.63 (m, 1H), 1.45(d, J=6.8 Hz, 3H).

[0412] Step 3. Synthesis of 77

[0413] To a solution of 76 (1.80 g, 10.6 mmol) in EtOH (120 ml) andether (60 ml) in an ice-water bath were added potassium hydroxide (0.178g, 3.17 mmol) and methyl vinyl ketone (1.11 g, 15.8 mmol). The mixturewas then warmed to RT and stirred for 16 hours. The mixture wasneutralized with 5% citric acid, concentrated, and partitioned betweenCH₂Cl₂ (2×150 ml) and aqueous sodium bicarbonate. The combined organicportion was washed with brine, dried (Na₂SO₄), and purified by columnchromatography (Hexanes gradient to EtOAc:Hexanes 1:20) to give 77 (1.50g, 64%). MS m/e 223 (M+H)⁺.

[0414] Step 4. Synthesis of 78 and 79

[0415] A mixture of 77 (1.50 g, 6.76 mmol), aminodiphenylmethane (1.49g, 8.11 mmol), and sodium triacetoxyborohydride (3.46 g, 16.4 mmol) indichloroethane (150 ml) was stirred at RT for 18 hours. The mixture wasdiluted with CH₂Cl₂ (150 ml) and washed with conc. NH₄OH (100 ml). Theorganic portion was dried (K₂CO₃) and purified by column chromatography(Hexanes gradient to EtOAc:Hexanes 1:33) to give 78 (0.440 g, 16%) and79 (0.322 g, 12%).

[0416] 78 ¹H-NMR (CDCl₃) δ7.42 (m, 4H), 7.30 (m, 4H), 7.21 (m, 2H), 6.87(m, 2H), 6.62 (m, 1H), 5.98 (m, 1H), 5.67 (m, 1H), 5.06 (s, 1H), 3.12(m, 1H), 1.88 (m, 2H), 1.60 (m, 1H), 1.29 (s, 3H), 1.20 (m, 2H).

[0417] 79 ¹H-NMR (CDCl₃) δ7.46 (m, 4H), 7.32 (m, 4H), 7.23 (m, 2H), 6.83(m, 2H), 6.62 (m, 1H), 5.99 (m, 1H), 5.69 (m, 1H), 5.08 (s, 1H), 3.10(m, 1H), 1.70 (m, 4H), 1.50 (m, 1H), 1.38 (s, 3H).

[0418] Step 5. Synthesis of 80

[0419] A mixture of 78 (0.440 g, 1.13 mmol), ammonium formate (1.30 g,20.7 mmol), and 10% Pd/C (0.090 g) in CH₃OH (30 ml) was stirred at RTfor 16 hours. The mixture was filtered and concentrated. The residue wastaken up in CH₂Cl₂ (100 ml), washed with conc. NH₄OH (20 ml), dried(K₂CO₃), concentrated, and purified by column chromatography (CH₂Cl₂gradient to 2M NH₃/CH₃OH: CH₂Cl₂ 1:20) to give 80 (0.200 g, 79%). ¹H-NMR(CDCl₃) δ6.87 (m, 2H), 6.61 (m, 1H), 2.73 (m, 1H), 2.21 (m, 2H), 1.73(m, 2H), 1.50 (m, 2H), 1.12 (s, 3H), 1.07 (m, 4H).

[0420] Step 6

[0421] To an ice-cooled solution of 80 (0.045 g, 0.20 mmol) and pyridine(200 μl, 2.45 mmol) in THF (5 ml) was added N,N′-disuccinimidylcarbonate (0.072 g, 0.28 mmol). The mixture was stirred at RT for 4hours. N-Methyl-1-(methylsulfonyl)-4-piperidineamine (0.042 g, 0.22mmol) was added at 0° C. and the mixture was stirred at RT for 16 hours.The mixture was diluted with CH₂Cl₂ (50 ml) and washed with 1N NaOH (20ml), 1N HCl (20 ml), saturated sodium bicarbonate, and brinesequentially. The organic portion was dried (MgSO₄), concentrated, andpurified by PTLC (CH₃OH: CH₂Cl₂ 1:20) to give 13A (0.005 g, 6%).

[0422] Using essentially the same procedure, 13B was prepared from 80.

[0423] Using essentially the same procedure, 13C and 13D were preparedfrom 79. Example ¹H NMR MS (M + H)⁺ 13A

(CDCl₃) δ 6.87(m, 2H), 6.64(m, 1H), 4.34(m, 1H), 4.05(m, 1H), 3.86(m,2H), 3.72(m, 1H), 2.77(s, 3H), 2.72(m, 2H), 2.62(s, 3H), 2.22(m, 2H),1.87(m, 2H), 1.5-1.8(m, 6H), 1.13(s, 3H), 1.10(m, 2H). 444 13B

(CDCl₃) δ 6.85(m, 2H), 6.64(m, 1H), 4.69(m, 1H), 4.40(m, 1H). 4.03(m,1H), 3.84(m, 1H), 3.73(m, 1H), 3.11(m, 1H), 2.59(s, 3H), 2.55(m, 1H),2.22(m, 2H), 2.08(s. 3H), 1.87(m, 2H), 1.4-1.7(m, 6H), 1.13(s, 3H),1.09(m, 2H). 408 13C

(CDCl₃) δ 6.87(m, 2H), 6.63(m, 1H), 4.39(m, 1H), 4.29(m, 1H), 3.89(m,2H), 3.66(m, 1H), 2.79(s, 3H), 2.76(m, 2H), 2.74(s, 3H), 1.94(m, 2H),1.6-1.9(m, 8H), 1.48(m, 2H), 1.25(s, 3H). 444 13D

(CDCl₃) δ 6.87(m, 2H), 6.63(m, 1H), 4.74(m, 1H), 4.47(m, 1H), 4.27(m,1H), 3.87(m, 1H), 3.68(m, 1H), 3.14(m, 1H), 2.70(s, 3H), 2.58(m, 1H),2.10(s, 3H), 1.94(m, 2H), 1.4-1.9(m, 10H), 1.25(s, 3H). 408

What is claimed is:
 1. A compound represented by the structural formula

or a pharmaceutically acceptable salt or solvate thereof, wherein: X isindependently N or C; Z is independently NR⁸ or CR³R⁹; D isindependently H, —OH, -alkyl or substituted -alkyl with the proviso thatwhen X is N, D and the X-D bond are absent; E is independently H, -alkylor substituted -alkyl, or D and E can independently be joined togethervia a —(CH₂)_(p)— bridge; Q is independently H, -alkyl or substituted-alkyl, or D, X, Q and the carbon to which Q is attached can jointlyform a 3 to 7-membered ring; g, j, k, m and n can be the same ordifferent and are independently selected; g is 0 to 3 and when g is 0,the carbons to which (CH₂)_(g) is shown connected are no more linked; jand k are independently 0 to 3 such that the sum of j and k is 0, 1, 2or 3; m and n are independently 0 to 3 such that the sum of m and n is1, 2,3, 4 or 5; p is 1 to 3; R¹ is 1 to 5 substituents which can be thesame or different, each R¹ being independently selected from the groupconsisting of hydrogen, hydroxy, halogen, haloalkyl, -alkyl, substituted-alkyl, -cycloalkyl, CN, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio,—NR⁵R⁶, —NO₂, —CONR⁵R⁶, —NR⁵COR⁶, —NR⁵CONR⁵R⁶ where the two R⁵ moietiescan be the same or different, —NR⁶C(O)OR⁷, —C(O)OR⁶, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, aryl and heteroaryl; R² is 1 to 6 substituents which can bethe same or different, each R² being independently selected from thegroup consisting of hydrogen, -alkyl, substituted -alkyl, alkoxy, andhydroxy, with the proviso that when X is N and R² is hydroxy or alkoxy,R² is not directly attached to a carbon adjacent to X; R³ isindependently hydrogen, -alkyl or substituted -alkyl; R⁴ is 1 to 6substituents which can be the same or different, each R⁴ beingindependently selected from hydrogen, -alkyl, substituted -alkyl,alkoxy, and hydroxy, with the proviso that when Z is NR⁸ and R⁴ ishydroxy or alkoxy, R⁴ is not directly attached to a carbon adjacent tothe NR⁸; R⁵ and R⁶ are independently hydrogen, -alkyl, substituted-alkyl or -cycloalkyl; R⁷ is independently -alkyl, substituted -alkyl or-cycloalkyl; R⁸ is independently selected from the group consisting ofhydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl,aryl, heteroaryl, aralkyl, heteroaralkyl, —SO₂R¹⁰, —SO₂NR⁵R¹¹, —C(O)R¹¹,—C(O)NR⁵R¹¹ and —C(O)OR¹⁰; R⁹ is independently hydrogen, -alkyl,substituted -alkyl, hydroxy, alkoxy, —NR⁵R¹¹, aryl, or heteroaryl; or R³and R⁹ can be joined together and with the carbon to which they areattached form a carbocyclic or heterocyclic ring having 3 to 7 ringatoms; R¹⁰ is -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl,aryl or heteroaryl; and R¹¹ is independently hydrogen, -alkyl,substituted -alkyl, -cycloalkyl, aryl or heteroaryl.
 2. The compound ofclaim 1 or a pharmaceutically acceptable salt or solvate thereof,wherein R¹ is 1 to 5 substituents which can be the same or different,each R¹ being independently selected from the group consisting of Cl,Br, I or F; X is N; D is absent and the X-D bond is absent; E is H; g is0; j is 1; k is 1; m is 2; n is 2; R² is H; R³ is methyl; R⁴ is H; and Zis NR⁸, where R⁸ is independently selected from the group consisting ofhydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl,aryl, heteroaryl, aralkyl, heteroaralkyl, —SO₂R¹⁰, —SO₂NR⁵R¹¹, —C(O)R¹¹,—C(O)NR⁵R¹¹ and —C(O)OR¹⁰.
 3. A compound represented by the structuralformula

or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ isdefined in the following table: R⁸ —COCH₃ —COCH₂CH₃

—COCH(CH₃)₂ —CO(CH₂)₂CH₃ —COOC(CH₃)₃ —SO₂CH₃ SO₂CH₂CH₃

—SO₂CH(CH₃)₂ —SO₂(CH₂)₂CH₃ —SO₂Ph.


4. A compound of claim 1 selected from the group consisting of

or a pharmaceutically acceptable salt or solvate of said compound.
 5. Acompound of claim 1 selected from the group consisting of

or a pharmaceutically acceptable salt or solvate of said compound.
 6. Acompound represented by the structural formula

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ is1 to 5 substituents which can be the same or different, each R¹ beingindependently selected from the group consisting of hydrogen, hydroxy,halogen, haloalkyl, -alkyl, substituted -alkyl, -cycloalkyl, CN, alkoxy,cycloalkoxy, alkylthio, cycloalkylthio, —NR⁵R⁶, —NO₂, —CONR⁵R⁶,—NR⁵COR⁶, —NR⁵CONR⁵R⁶ where the two R⁵ moieties can be the same ordifferent, —NR⁶C(O)OR⁷, —C(O)OR⁶, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, aryl andheteroaryl; R³ is independently hydrogen or -alkyl; and R⁸ isindependently selected from the group consisting of hydrogen, -alkyl,substituted -alkyl, -cycloalkyl, -alkylcycloalkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, —SO₂R¹⁰, —SO₂NR⁵R¹¹, —C(O)R¹¹, —C(O)NR⁵R¹¹ and—C(O)OR¹⁰.
 7. A compound of claim 6 selected from the group consistingof

or a pharmaceutically acceptable salt or solvate of said compound.
 8. Acompound represented by the structural formula

or a pharmaceutically acceptable salt or solvate there of, wherein R¹ is1 to 5 substituents which can be the same or different, each R¹ beingindependently selected from the group consisting of hydrogen, hydroxy,halogen, haloalkyl, -alkyl, substituted -alkyl, -cycloalkyl, CN, alkoxy,cycloalkoxy, alkylthio, cycloalkylthio, —NR⁵R⁶, —NO₂, —CONR⁵R⁶,—NR⁵COR⁶, —NR⁵CONR⁵R⁶ where the two R⁵ moieties can be the same ordifferent, —NR⁶C(O)OR⁷, —C(O)OR⁶, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, aryl andheteroaryl; R³ is independently hydrogen or -alkyl; and R⁸ isindependently selected from the group consisting of hydrogen, -alkyl,substituted -alkyl, -cycloalkyl, -alkylcycloalkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, —SO₂R¹⁰, —SO₂NR⁵R¹¹, —C(O)R¹¹, —C(O)NR⁵R¹¹ and—C(O)OR¹⁰.
 9. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1 in combination with apharmaceutically acceptable carrier.
 10. A method of treating ametabolic disorder, eating disorder or diabetes comprising administeringan effective amount of a compound of claim 1 to a mammal in need of suchtreatment.
 11. A pharmaceutical composition, which comprises aneffective amount of a compound as, defined in claim 1 and apharmaceutically acceptable carrier thereof.
 12. A method of treatingmetabolic or eating disorders comprising administering to a mammal inneed of such treatment a therapeutically effective amount of a compoundof claim 1 or a pharmaceutically acceptable salt of said compound. 13.The method of claim 10 wherein said metabolic disorder is obesity. 14.The method of claim 10 wherein said eating disorder is hyperphagia. 15.A method of treating disorders associated with obesity comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt of said compound.
 16. The method of claim 15 whereinsaid disorders associated with obesity are Type II Diabetes, insulinresistance, hyperlipidemia and hypertension.
 17. A pharmaceuticalcomposition which comprises a therapeutically effective amount of acomposition comprising: a first compound, said first compound being acompound of claim 1 or a pharmaceutically acceptable salt of saidcompound; a second compound, said second compound being an anti-obesityand/or anorectic agent such as a β₃ agonist, a thryomimetic agent, ananorectic agent or an NPY antagonist; and a pharmaceutically acceptablecarrier thereof.
 18. A method of treating a metabolic or eating disorderwhich comprises administering to a mammal in need of such treatment anamount of a first compound, said first compound being a compound ofclaim 1 or a pharmaceutically acceptable salt of said compound; a secondcompound, said second compound being an antiobesity and/or anorecticagent such as a β₃ agonist, a thryomimetic agent, an anorectic agent oran NPY antagonist; wherein the amounts of the first and second compoundsresult in a therapeutic effect.
 19. A pharmaceutical composition whichcomprises a therapeutically effective amount of a compositioncomprising: a first compound, said first compound being a compound ofclaim 1 or a pharmaceutically acceptable salt of said compound; a secondcompound, said second compound being an aldose reductase inhibitor, aglycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, aprotein tyrosine phosphatase 1B inhibitor, a dipeptidyl proteaseinhibitor, insulin (including orally bioavailable insulin preparations),an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such astroglitazone, rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea,glipazide, glyburide, or chlorpropamide; and a pharmaceuticallyacceptable carrier therefor.
 20. A pharmaceutical composition made bycombining the compound of claim 1 and a pharmaceutically acceptablecarrier therefor.
 21. A process for making a pharmaceutical compositioncomprising combining a compound of claim 1 and a pharmaceuticallyacceptable carrier.